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Abstract

Background

A novel formulation of diclofenac, complexed with hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes.

Methods

This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection.

Results

A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild.

Conclusions

The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.

Trial registration: EudraCT Registration No. 2017-004828-29.

Keywords

Diclofenac sodium subcutaneous administration self-administered migraine attack randomized controlled trials

Introduction

Several drugs are effective for the acute treatment of migraine attacks (1 –6), including analgesics (paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs), triptans (5-HT_1B/D receptor agonists) and calcitonin gene-related peptide (CGRP) receptor antagonists. These drugs, however, are not effective in every patient or in all attacks in the same patient. Besides pharmacodynamic reasons, pharmacokinetic problems may limit the efficacy of abortive migraine medications. The earlier the oral antimigraine drugs are taken, the more positive the treatment outcome is (7). However, nausea and/or vomiting, common during a migraine attack, may reduce the gastrointestinal absorption of oral medications (3,8). Gastroparesis (gastric stasis) resulting in delayed emptying of the stomach may favour delayed absorption of oral drugs, even in patients without marked nausea or emesis (9,10). The delay of otherwise effective acute migraine medications to bind their specific target may limit the effectiveness of the treatment (11). Hence, there is a need to develop non-oral new formulations to accelerate the absorption and, therefore, the beneficial effect of aborting drug-resistant migraine attacks.

NSAIDs, including diclofenac and ketorolac, are effective agents for acute migraine treatment (12 –15). Currently available NSAID formulations include oral, intranasal, rectal, intramuscular (IM) or intravenous (IV) routes (16,17). Although rectal administration may circumvent some limitations of oral agents, drug absorption after rectal administration is poorly predictable. Furthermore, patients prefer IM injection of an NSAID over its rectal administration (18). Although IM and IV injections provide marked efficacy, they are not easily self-administered (19). In contrast, subcutaneous (SC) formulations may provide a viable alternative as they are rapidly absorbed from the injection site, bypass the gastrointestinal tract, and can be self-administered (19). The superiority of SC formulations over oral, intranasal and rectal formulations has been reported for sumatriptan in treating acute migraine attacks (20).

Diclofenac is a phenylacetic acid derivative NSAID that primarily inhibits cyclooxygenase (COX) enzymes (21) with a higher selectivity for COX-2 than for COX-1 (21). Recently, a novel formulation of diclofenac sodium suitable for SC or IM injection (Akis®, Dicloin®, IBSA Farmaceutici Italia Srl) has been developed using the complexing agent hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer (22), allowing the use of a smaller volume of injection (1 mL) in a ready-to-use formulation that can be self-administered subcutaneously or intramuscularly (22 –24). Diclofenac/HPβCD is available in several European countries, where it is indicated for use in adults with acute forms of pain (25) in the three doses of 25, 50, and 75 mg/mL dissolved in an aqueous volume of 1 mL (24).

In clinical trials, SC or IM diclofenac/HPβCD showed analgesic efficacy in moderate-to-severe acute postoperative pain following dental surgery or minor orthopaedic surgery, in moderate-to-severe neuropathic pain, and in relieving pain associated with knee osteoarthritis (23,26 –29). Data from more than 20 clinical studies show that the new diclofenac/HPβCD formulation provides rapid and effective relief of acute pain while retaining the pharmacokinetic and efficacy/safety profiles of other medicinal products not containing cyclodextrins (23,26).

Here, we report the results of a proof-of-concept pilot study designed to evaluate the efficacy, safety and tolerability of three doses of self-administered SC diclofenac/HPβCD in the acute treatment of migraine.

Materials and methods

Study design and objectives

This was a phase 2, multicentre, double-blind, four-arm, parallel-group, randomized, placebo-controlled, dose-finding pilot study comparing the efficacy, safety and tolerability of a single self-administered SC injection of one of three different doses (25/50/75 mg/1 mL) of diclofenac/HPβCD with that of placebo in the treatment of an acute migraine attack of moderate-to-severe intensity. The parallel-group superiority trial design using a physiological solution as a placebo was chosen as more direct means of demonstrating the clinical and statistical effectiveness of the investigational medicinal product, and the study design was developed in accordance with current guidelines and recommendations on clinical investigation of medicinal products for the treatment of migraine (30 –32).

The primary objective of the study was to evaluate the efficacy of the SC diclofenac injection compared with placebo in migraine of moderate-to-severe intensity. A total of 128 subjects were to be randomized at 9 sites in Italy, with a mean of about 13 subjects/site. There was a screening period of a maximum of 21 days and a follow-up period of a maximum of 15 days (plus a 3-day window). The duration of the study per subject could vary depending on the occurrence of the migraine attack. Visit 2/End of Study Visit was scheduled as soon as possible after the patient’s call, which was expected within 72 hrs from the migraine attack (see study flow chart, Figure 1).

Figure 1.

Flow chart of the study procedures. Note: efforts were to be taken in order to shorten the V0-V1 and D1-V2 periods. R: Randomisation; randomisation ratio 1:1:1:1.

Ethical considerations

The trial was designed and monitored according to the ethical principles of the International Conference on Harmonisation (ICH), the Consolidated Guideline on Good Clinical Practice (GCP), and the Declaration of Helsinki and following all other requirements of local laws. The study protocol was registered with the Agenzia Italiana del Farmaco (AIFA), and Independent Ethics Committee approval was obtained from each participating site before starting any study-related procedure. All patients provided written informed consent before their participation. Project Management and monitoring of the study were carried out by the local contract research organisation (CRO), Pharmaceutical Development & Services S.r.l., Firenze, Italy. The study was registered with the European Union Clinical Trials Register (EudraCT Number: 2017-004828-29). No formal protocol amendments were generated during the conduct of the study.

Patient population

Adults attending the out-patient facilities of the centres involved in the trial and aged between 18 and 65 years with a diagnosis of migraine according to ICHD-3 criteria (3) were eligible for participation if the onset of their migraine was before 50 years of age and they had: a history of migraine for ≥1 year; ≥3 months of well-documented retrospective history of migraine attacks that typically lasted between 4 and 72 hours if untreated/treated unsuccessfully and with migraine episodes separated by ≥48 hours of headache pain freedom; 2 to 8 migraine attacks per month with moderate-to-severe headache and ≤15 days of headache per month. Patients could continue one migraine preventive medication, provided that it was started at least 3 months before enrolment in the study, and the dose was kept stable during the entire study duration. Previous migraine preventive drugs needed to be withdrawn at least 1 month before inclusion (or at least 2 half-lives for compounds with more prolonged effects). The use of reliable contraception was required for women of childbearing age. The main exclusion criteria were: clinically relevant psychiatric or neurological disorders, acute pain syndromes, anaemia, asthma, uncontrolled hypertension, or cerebrovascular or peripheral arterial disease, hepatic or renal failure, overuse of acute medications in the 3 months before inclusion, or any bleeding risk. Patients taking ongoing medication with drugs known or suspected of adversely affecting the investigational medicinal product were excluded if the pathology under treatment was considered unstable and likely to contraindicate the concurrent administration of the investigational medicinal product.

Study procedures

Patients were randomized in a ratio of 1:1:1:1 to one of four parallel treatment groups: diclofenac/HPβCD 25 mg (D25), diclofenac/HPβCD 50 mg (D50), diclofenac/HPβCD 75 mg (D75), or placebo (NaCl 0.9%). The three dosage strengths (25, 50 and 75 mg/mL) of diclofenac sodium are already approved in the European Union for pain management, and the route of administration is supported by pharmacokinetic evaluation (22).

The randomization schedule was prepared by the Data Management and Statistics Department of the sponsor, (IBSA Institut Biochimique S.A.), according to standard operating procedures, using validated software (SAS Institute Inc., Cary, NC, USA). Subjects, investigator, sponsor, CRO team, and site personnel were blinded to the treatment group assignment, and strict procedures were adopted to maintain blinding throughout the study. The diclofenac sodium and placebo solutions were provided as identical-appearing standard prefilled syringes.

The investigational medicinal product (IMP) consisted of an aqueous solution of diclofenac sodium in a formulation containing hydroxypropyl β-cyclodextrin (HPβCD) as a complexing agent. HPβCD is a biologically inert substance that does not influence the analgesic and anti-inflammatory activity of diclofenac.

Treatment was self-administered at home as a single SC injection, and patients were directed that the injection had to be performed into the subcutaneous tissue of the abdomen or the anterior thigh at the first new migraine attack occurring after the baseline visit. Subjects were required to perform the injection at the earliest time they experienced a migraine headache of moderate-to-severe intensity, defined as a response of 2–3 on a four-point Likert-like scale where 3 = severe, 2 = moderate, 1 = mild, and 0 = none. The investigators provided patients with detailed instructions and training on correctly performing an SC injection. The use of a rescue medication was allowed, if required, from 2 hours after the injection of the investigational product.

Concomitant medications were recorded in an electronic case report form throughout the study. These included the patient’s usual medication for migraine attacks, which was allowed as rescue medication, drugs for symptomatic relief of nausea/vomiting, regular treatments for concomitant conditions unless listed among prohibited treatments or with known drug-drug interactions with NSAIDs, and the migraine preventive migraine treatment, if used. The use of diclofenac or other NSAIDs or COX-2 inhibitors as rescue medication was carefully evaluated by the investigator and avoided when considered to be contraindicated. Patients were not allowed to use rescue medication for migraine within the first 2 hours after study drug injection. Any medication known or suspected to interfere with the investigational medicinal product or new migraine treatments and antipsychotics, benzodiazepines and anticonvulsants for conditions other than migraine prophylaxis, were prohibited.

This was a single-dose study. The investigator checked the patient’s compliance with treatment at the post-dose visit. The study schedule comprised three visits that the investigator carried out at each investigational study site. The first visit (Visit 0) included collecting demographic information, medical and migraine history, physical examination, evaluation of vital signs, blood and urine collection for laboratory examination, training, and delivery of the patient diary. Patients who fulfilled inclusion criteria underwent a second physical examination and check of vital signs and prior/concomitant medications, and were trained in the use of the syringe and were then randomized to treatment during the second visit (Visit 1; D0).

The day of the migraine attack was considered to be D1; within 72 hours, the subject had to contact the site to organize the end-of-study visit (Visit 2/D1 + 15 days), which had to be scheduled as soon as possible. Patients were required to complete a specific diary to capture changes in health status and concomitant medications; the investigators or their authorised delegates recorded data generated in the trial in an e-case report form using a validated electronic data capture system (Oracle Clinical v.5.0.1, Oracle Corporation, Texas, USA). Any adverse events (AEs) or adverse drug reactions (ADRs) were recorded, starting from the day the informed consent was provided. An unscheduled visit could be performed at any time after screening for safety reasons.

Outcome measures

The primary efficacy variable was the percentage of patients who were pain-free (pain score = zero) at 2 hours post-study drug injection. Patients were asked to record in the diary the intensity of the pain associated with the migraine at baseline (before injection), and 30-, 60-, 90-, and 120-minutes post-injection, using a four-point Likert-like scale where 3 = severe; 2 = moderate; 1 = mild; 0 = none. The key secondary endpoints included the absence of photophobia/phonophobia/nausea/vomiting at 2 hours post-injection, absence of nausea at 12, 24 and 48 hours post-injection, sustained pain freedom from 2 to 12, 24 and 48 hours post-injection, incidence of relapse, use of rescue medication within the 2–48 hour period post-injection, patient functioning at 2 hours post-injection, patient satisfaction, time to pain freedom, and global impression of the study treatment. The safety variables included treatment-emergent AEs; serious adverse events (SAEs); serious ADRs; severity of AEs; classification of relationship with study drug; local tolerability. Vital signs and changes in laboratory parameters were assessed at Visit 0 and at the End of Study Visit.

Statistical methods

The study sample size was based on an a priori calculation, using the software NQuery Advisor version 7.0, using assumptions derived from results observed in previous clinical investigations for the number of migraine attacks alleviated 2 hours after drug administration (IBSA data on file). These data indicated that a total of 124 patients (rounded to 128 patients; 32 in each of the 4 groups) were required to detect treatment effects of 25% for placebo and 60% for diclofenac sodium with a two-sided α = 5% and a power of 80%. All calculations relating to the study protocol were reviewed and confirmed at the Data Management and Statistics Department of the sponsor by the statistician who performed the statistical analysis. Patients were to be randomized at nine investigational sites in Italy. All randomized patients who received one injection of diclofenac sodium or placebo and having at least one post-treatment pain intensity assessment were included in the intention-to-treat (ITT)/full analysis set (FAS) and safety set. The per-protocol (PP) population included all subjects from the ITT population without any major protocol deviation. The primary and secondary efficacy endpoints were analyzed in the ITT population and analyses were repeated in the PP population. Safety parameters were analyzed in the safety population.

In the analysis of the primary endpoint, each dose was individually compared to placebo using the Chi-Square test. The 95% confidence interval (CI) for the differences in the percentage of patients who were pain-free between the treatment groups was also calculated.

All analyses of secondary endpoints were performed using ordinary hypothesis testing methods based on the null hypothesis of no difference. The Chi-Square test was used for the comparisons between groups of categorical variables. Time to pain freedom, evaluated as the speed of onset of therapeutic effect, was analyzed using the Kaplan-Meier life-table methods; log-rank tests were used for hypothesis testing. The patient’s global impression of the study drug using a 5-point scale was compared between treatment groups using the Mantel-Haenszel Chi-Square test.

For continuous variables, the differences between groups were analyzed by analysis of variance (ANOVA) with the treatment group as a class variable. Non-ordered categorical variables for the four groups were compared using the Kruskal-Wallis test and/or a Chi-square test. All statistical analyses and data processing were performed using SAS® Software (SAS Institute Inc., Cary, NC, USA) release 9.4 for Windows. A two-sided probability level of ≤0.05 was considered to be statistically significant when comparing treatments.

Results

Demographics

The study was conducted at nine investigational study sites in Italy. A total of 139 patients were screened, and 129 attended Visit 1, while 9 patients were screening failures and 1 voluntarily withdrew from the study (Figure 2). One hundred and twenty-eight patients were randomized to the assigned treatment group and 122 were treated and returned for Visit 2 (end-of-study visit). The first study subject was enrolled on 20 September 2018, and the last patient completed on 22 November 2019. All treated patients had at least one post-treatment pain intensity assessment and were included in both the safety and the ITT populations (Figure 2). Subject demographic and other characteristics are presented in Table 1. All patients were of the Caucasian race. There were no statistically significant between-group differences for age, sex distribution, distribution of migraine-associated symptoms, ethnic origin and height. The D50 group differed from the placebo group as regards body weight (p = 0.0461) and body mass index (p = 0.0302). The medical history of relevance was generally well balanced across treatment groups.

Figure 2.

Patient disposition. D25, D50, D75: Diclofenac 25, 50, 75 mg/1 mL.

Table 1.

Demographic and clinical characteristics (intention-to-treat population).

Variable	Diclofenac 25 mg (N = 31)	Diclofenac 50 mg (N = 30)	Diclofenac 75 mg (N = 30)	Placebo (N = 31)
Age, years
Mean	40.10 ± 11.36	38.80 ± 12.93	41.93 ± 10.43	43.26 ± 10.72
Median	41.00 (19–59)	40.00 (20–58)	42.00 (21–59)	46.00 (20–65)
ANOVA p-values vs Placebo	0.2642	0.1474	0.6267	–
Gender
Female	26 (83.9)	24 (80.0)	28 (93.3)	26 (83.9)
Male	5 (16.1)	6 (20.0)	2 (6.7)	5 (16.1)
Chi² p-values vs Placebo	1.000	0.6942	0.2464	–
Height, meters
Mean	1.68 ± 0.09	1.68 ± 0.07	1.66 ± 0.06	1.68 ± 0.08
Median	1.66 (1.55–1.86)	1.68 (1.55–1.82)	1.66 (1.50–1.78)	1.68 (1.57–1.85)
ANOVA p-values vs Placebo	0.9878	0.7673	0.2545	–
Body weight, kg
Mean	65.99 ± 9.14	61.38 ± 10.67	63.08 ± 9.38	67.43 ± 12.43
Median	67.00 (46–82)	61.50 (40–78)	61.50 (48–90)	64.00 (45–100)
ANOVA p-values vs Placebo	0.6047	0.0461	0.1290	–
Body mass index, kg/m²
Mean	23.41 ± 3.33	21.78 ± 3.15	22.89 ± 3.38	23.80 ± 3.91
Median	22.66 (17.97–29.30)	21.75 (16.33–27.55)	22.63 (17.99–31.51)	22.53 (18.03–34.29)
ANOVA p-values vs Placebo	0.6718	0.0302	0.3376	–
Age at onset of migraine, years
Mean	17.16 ± 8.77	19.37 ± 7.73	17.33 ± 5.70	20.55 ± 8.70
Median	15.00 (6–43)	17.50 (6–40)	17.00 (7–34)	18.00 (10–40)
ANOVA p-values vs Placebo	0.1320	0.5774	0.0941	–
Associated symptoms at onset
Nausea	30 (96.8)	26 (86.7)	30 (100.0)	27 (87.1)
Fisher p-values vs Placebo	0.3540	1.0000	0.1128	–
Phonophobia	30 (96.8)	25 (83.3)	26 (86.7)	28 (90.3)
Fisher p-values vs Placebo	0.6124	0.4729	0.7072	–
Photophobia	29 (93.5)	26 (86.7)	30 (100.0)	27 (87.1)
Fisher p-values vs Placebo	0.6713	1.0000	0.1128	–
Vomiting	15 (48.4)	12 (40.0)	18 (60.0)	13 (41.9)
Fisher p-values vs Placebo	0.6098	0.8779	0.1583	–
Number of attacks per month^a
Mean ± SD (range)	4.00 ± 1.51 (2–7)	4.23 ± 1.85 (2–8)	4.33 ± 1.69 (2–8)	4.68 ± 1.87 (2–8)
Kruskal-Wallis p-values vs Placebo	0.2986	0.3115	0.4856	–
Duration of attacks, hours
Mean	30.26 ± 18.38	33.00 ± 18.00	30.80 ± 16.76	33.61 ± 18.31
Median	24.00 (4–72)	36.00 (4–72)	24.00 (4–72)	24.00 (5–72)
ANOVA p-values vs Placebo	0.4744	0.8956	0.5310

Unless otherwise indicated, data are mean ± standard deviation (SD), median (range) or no. (%). ANOVA analysis of variance.

^aAttacks of moderate-to-severe intensity over the previous three months.

Almost half of the patients (46.7%) took a migraine preventive medication at baseline, without statistically significant difference between groups. There were no significant between-group differences as regards history of moderate-to-severe intensity migraine attacks or previous and concomitant medications use.

Efficacy

The percentage of patients who were pain-free at 2 hours (primary efficacy endpoint) in the D50 group (n = 14, 46.7%) was significantly higher than the placebo group (n = 5, 16.1%) (p = 0.01) (Figure 3). The percentage of pain-free patients at 2 hours in the D25 and D75 groups was numerically but not statistically significantly higher than the placebo group (n = 9, 29.0% and n = 10, 33.3%, respectively) (Table 2).

Figure 3.

Primary efficacy endpoint. Patients pain-free at 2 hours after injection in the intention-to-treat population (n = 122).

Table 2.

Primary and secondary efficacy endpoints in the intention-to-treat population (N = 122).

Variable	Diclofenac 25 mg (N = 31)	Diclofenac 50 mg (N = 30)	Diclofenac 75 mg (N = 30)	Placebo (N = 31)
Pain-free at 2 hours post-dose^a	9 (29.0)	14 (46.7)	10 (33.3)	5 (16.1)
p-value vs. placebo	0.2244	0.0100	0.1188
Absence of photophobia at 2 hours post-dose	19 (61.3)	24 (80.0)	22 (73.3)	16 (51.6)
p-value vs. placebo	0.442	0.0197	0.0801
Absence of phonophobia at 2 hours post-dose	23 (74.2)	24 (80.0)	21 (70.0)	22 (71.0)
p-value vs. placebo	0.7759	0.4128	0.9340
Absence of nausea at 2 hours post-dose	18 (58.1)	26 (86.7)	23 (76.7)	19 (61.3)
p-value vs. placebo	0.7957	0.0243	0.1948
Absence of vomiting at 2 hours post-dose	29 (93.5)	29 (96.7)	29 (96.7)	31 (100.0)
p-value vs. placebo	0.1506	0.3054	0.3054
Sustained pain freedom from 2 to 12 hours post-dose	7 (22.6)	11 (36.7)	8 (26.7)	3 (9.7)
p-value vs. placebo	0.1672	0.0122	0.0844
Sustained pain freedom from 2 to 24 hours post-dose	7 (22.6)	10 (33.3)	7 (23.3)	3 (9.7)
p-value vs. placebo	0.1672	0.0241	0.1498
Sustained pain freedom from 2 to 48 hours post-dose	6 (19.4)	10 (33.3)	7 (23.3)	3 (9.7)
p-value vs. placebo	0.2794	0.0241	0.1498
Relapse within 48 hours post-dose (pain-free at 2 hours)	3 (30.0)	4 (28.6)	3 (30.0)	2 (40.0)
p-value vs. placebo	0.8030	0.7098	0.8030
Rescue medication required with 48 hours post-dose	21 (67.7)	11 (36.7)	16 (53.3)	23 (74.2)
p-value vs. placebo	0.5758	0.0032	0.0898
Able to function normally at 2 hours post-dose	9 (29.0)	13 (43.3)	11 (36.7)	5 (16.1)
p-value vs. placebo	0.2244	0.0199	0.0683

Data are expressed as no. (%). Bolded values: Chi² test vs Placebo: p-value < 0.05.

^aPrimary efficacy endpoint. All treated migraine attacks were of moderate-to-severe intensity.

Consistent with the primary efficacy endpoint, the absence of photophobia or absence of nausea at 2 hours after the study drug injection (Figure 4), sustained pain freedom from 2 to 12-, 24- and 48-hours after the injection (Figure 5), and ability to function normally at 2 hours after the injection, were higher in the D50 group than in the placebo group. The diclofenac/HPβCD 50 mg dose also showed the shortest time to pain freedom compared to the other three groups, though the pattern was not statistically significant. The percentage of patients requiring a rescue medication in the interval 2-48 hours after the injection was significantly higher in the placebo group compared to the D50 group (Figure 6).

Figure 4.

Proportion of patients free of nausea or photophobia 2 hours after injection in the intention-to-treat population (n = 122).

Figure 5.

Sustained pain relief at 12, 24, and 48 hours after injection in the intention-to-treat population (n = 122).

Figure 6.

Use of rescue medication over time after injection in the intention-to-treat population (n = 122).

Although numerically superior to placebo in most secondary efficacy endpoints, the differences between the D25 and D75 doses did not reach statistical significance, and between-group differences for some other secondary endpoints did not reach statistical significance (Table 2).

A good or excellent global impression was reported by 11 patients (35.5%) in the D25 group, 16 (53.3%) in the D50 group, 7 (23.3%) in the D75 group and 9 (29.0%) in the placebo group. A very poor global impression was reported by 2 patients (6.5%) in the D25 group, 3 (10.0%) in the D50 group, 3 (10.0%) in the D75 group and 11 (35.5%) in the placebo group. The overall difference between groups was statistically significant (p = 0.0427).

Safety and tolerability

A total of 102 treatment-emergent adverse events (TEAEs) were reported in 18 patients (58.1%) in the D25 group (26 events), 16 (53.3%) in the D50 group (28 events), 19 (63.3%) in the D75 group (38 events) and 7 patients (22.6%) in the placebo group (10 events). A summary of AEs is presented in Table 3.

Table 3.

Summary of adverse events in the safety analysis set (N = 122).

	Diclofenac 25 mg (N = 31)	Diclofenac 50 mg (N = 30)	Diclofenac 75 mg (N = 30)	Placebo (N = 31)
Patients with ≥1 adverse event, no. (%)^a
Any TEAE	18 (58.06)	16 (53.33)	19 (63.33)	7 (22.58)
Treatment-related	18 (58.06)	16 (53.33)	19 (63.33)	7 (22.58)
Mild	15 (48.39)	15 (50.00)	18 (60.00)	6 (19.35)
Moderate	2 (6.45)	3 (10.00)	4 (13.33)	1 (3.23)
Severe	1 (3.23)	0 (0.00)	0 (0.00)	0 (0.00)
SAE	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
AEs leading to study withdrawal	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)

^a A patient may have more than one occurrence of an adverse event. AE, adverse events; SAE, serious adverse events; TEAE, treatment emergent adverse events.

The most commonly reported treatment-related TEAE was injection site pain, which occurred in 17 patients (54.8%) in the D25 group, 11 (36.7%) in the D50 group, 15 (50.0%) in the D75 group, and 5 (16.1%) in the placebo group. Other treatment-related TEAEs mainly consisted of other local reactions at the site of injection. The majority of TEAEs were of mild severity (Table 3). There was only 1 TEAE of severe intensity, injection site pain in a patient in the D25 group.

At the end-of-study visit, laboratory parameters and mean vital signs (systolic and diastolic blood pressure, heart rate) were normal in the overall population. One patient, in the D50 group, reported an increase in transaminases two weeks after the injection, at which time aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were approximately 2.7 and 2.5 times the upper limit of normal. Levels of transaminases had returned to within the normal range when checked approximately two months after the injection.

The percentage of patients with good or excellent overall opinion on local tolerability was higher in the placebo group than in the three diclofenac groups at any time point (both immediately after the injection and 2-, 12-, 24- and 48-hours later). Conversely, more patients in all three diclofenac groups than in the placebo group had a very poor, poor or fair overall opinion on local tolerability.

Discussion

The objective of this dose-finding pilot study was to evaluate the efficacy, safety and tolerability of a single SC injection of three different doses (25, 50 and 75 mg/1 mL) of diclofenac/HPβCD compared to placebo in the acute treatment of a single migraine attack of moderate-to-severe intensity. The primary endpoint was satisfied by the D50 dose that proved significantly more effective than placebo (p = 0.01).

Diclofenac is one of the most prescribed NSAIDs worldwide for the treatment of inflammatory disease and pain (33,34) and has an established role in the treatment of acute migraine. Oral diclofenac potassium in tablet, sachet or solution formulations has previously been shown to be effective, fast-acting, and well-tolerated in the treatment of acute migraine attacks as an alternative to sumatriptan or other oral migraine therapies (35 –39). Similarly, oral diclofenac epolamine is more effective than placebo in mild-to-moderate acute migraine, reducing time to attack resolution, impact on ability to work, and sensitivity to light and noise, compared with placebo (40). Diclofenac can also be administered by the SC or IM route (41,42), and novel formulations of diclofenac sodium complexed with a cyclodextrin as a solubility enhancer (diclofenac/HpβCD) have been developed (22 –24). Diclofenac/HPβCD by SC or IM injection has previously been reported to be safe and effective in relieving other pain conditions (23,26 –29). In addition, analysis of pharmacokinetic studies shows that the pharmacokinetic profile of SC diclofenac/HPβCD is comparable to that of IM or IV administration of diclofenac formulations not containing cyclodextrins (23,24,26).

Here, we show that the 50 mg SC formulation of diclofenac/HPβCD is also effective in the acute treatment of a migraine attack and provides a safe, effective and well-tolerated option to current medications for the treatment of acute migraine. Patients self-administered the single-dose SC injection at home. Self-administration proved to be safe and demonstrated that, if correctly trained, there is no additional risk with this new route of diclofenac administration.

In our study, all three diclofenac doses were more effective than placebo in the percentage of pain-free patients at 2 hours after the study drug injection, the primary efficacy endpoint. This result supports the analgesic effectiveness of all dosages of the SC diclofenac formulation. However, the diclofenac 50 mg/mL unit dose had the best efficacy/safety profile, delivering the highest percentage of pain-free patients at 2 hours after injection, and was significantly superior to placebo (p = 0.01).

Similarly, the diclofenac/HPβCD formulation was more effective than placebo in many secondary efficacy endpoints, including the absence of photophobia or absence of nausea at 2 hours after injection, sustained pain freedom, and ability to function normally at 2 hours after injection. Time to pain freedom was numerically shorter with the diclofenac/HPβCD 50 mg dose, and the 50 mg dose was also associated with a significantly lower requirement for rescue medication.

The percentage of patients satisfied or extremely satisfied with treatment and patients who had a good or excellent global impression of the study treatment was higher in the D50 group than in the other two diclofenac groups or placebo. Conversely, more patients in the placebo group than in the three diclofenac groups had a very poor global impression of the study treatment, with the overall difference between groups statistically significant in the ITT population.

There was a higher rate of reporting of TEAEs and treatment-related TEAEs in the three diclofenac groups than in the placebo group. However, all diclofenac strengths had an acceptable local tolerability profile for all diclofenac dose strengths. Most treatment-related TEAEs consisted of injection site pain of mild intensity, in line with expectations for an SC injection, and there were no serious TEAEs or AEs leading to withdrawal from the study.

This was a randomized, placebo-controlled, study with a study protocol designed to prevent bias, including underpower. The observation that the 25 mg dose failed to meet the primary endpoint may be due to the insufficient efficacy of this strength to ameliorate severe migraine attacks and suggests that the 50 mg dose is the minimum therapeutic dose. This is in line with good clinical practice to use NSAIDs at the lowest effective dose and for the shortest duration. Less apparent is the failure of the highest dose (75 mg). However, a possible explanation of the failure may derive from the limited number of patients enrolled in each group and the high intrinsic rate of the placebo response observed after parenteral administration that may have prevented the observation of a statistically significant difference with the 75 mg dose. In agreement with this hypothesis, the rates of pain freedom at 2 hours after the study drug injection were marginally lower than those estimated for the sample size calculation in all four treatment groups. Nonetheless, the positive results of our pilot study with the 50 mg dose support further investigation of these observations in a larger patient population, including the identification of the most effective dose.

Conclusions

This study provides Class II evidence that a SC injection of diclofenac sodium (50 mg/mL) is effective for the treatment of acute migraine in patients with moderate-to-severe migraine pain. Because of its rapid onset of action and effect, this therapeutic option may be superior to oral drugs when gastrointestinal absorption cannot be assured because of the concomitant presence of nausea and/or vomiting.

Article highlights

Acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes have practical limitations and issues of patient preference.

Formulating diclofenac with a cyclodextrin as a solubility enhancer allows the use of a smaller volume of injection in a ready-to-use formulation for self-administered subcutaneous treatment of acute migraine.

Subcutaneous diclofenac 50 mg was significantly more effective than placebo in treating an acute migraine attack.

This novel formulation of diclofenac represents a valuable self-administered option with good tolerability and patient satisfaction.

Footnotes

Acknowledgements

This article is dedicated to the memory of our colleague and friend, Carlo Lisotto. The authors thank Ray Hill, an independent medical writer, who provided technical writing support funded by IBSA Institut Biochimique S.A. (Lugano, Switzerland).

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PG: personal fees from Allergan, Eli Lilly, Novartis, Amgen, Teva, grants from Amgen, Teva, Eli-Lilly, Allergan, Chiesi; and has been a member of the Scientific Advisory Board for Endosome Therapeutics and Founder and shareholder of FloNext srl, a spinoff of the University of Florence; FDC: personal fees from Lilly, Teva, Novartis; SB: fees from IBSA (consultancy) and Teva (advisory board); SC received travel grants, honoraria for advisory boards, speaker panels or clinical investigation studies from Novartis, Teva, Lilly, Allergan, IBSA, Amgen, Angelini and Lundbeck; GP received honoraria for advisory boards from Teva and received speaker honoraria from Eli Lilly, Novartis, Teva and Allergan; VF participated in Advisory Board from Teva, received speaker honoraria from Novartis, Eli Lilly and Teva and was a consultant for Eli Lilly and Allergan; FF: collaborations with Angelini, Cristalfarma, IBSA, Eli Lilly, Novartis, Teva; PDF: collaborations with Cristalfarma, IBSA, Novartis, Teva; GDA: collaborations with IBSA and Cristalfarma; CT: personal fees from Allergan, Abbvie, Eli Lilly, Lundbeck, Novartis and Teva and the PI or collaborator in clinical trials sponsored by Abbvie, Alder, Amgen, Eli-Lilly, IBSA, Lundbeck, Novartis and Teva and has received grants from the European Commission, the Italian Ministry of Health and the Italian Ministry of Education, University and Research; GS: honoraria for the participation in advisory boards or for oral presentations from: Eli-Lilly, Novartis and Teva. She is PI or sub-investigator in clinical trials sponsored by Novartis, Eli-Lilly, Teva, Allergan, and Lundbeck; MMC: personal fees from Allergan, Eli Lilly, Teva, Novartis, and IBSA; CB received honoraria from Allergan, Teva, Eli Lilly and Novartis; GT received advisory board fees and research support from Biogen, Merck, Lilly, Novartis, Abbvie, Lundbeck; AR received speaker honoraria from Allergan, Lilly, Novartis and Teva and serves as an associate editor for the Headache Medicine and Facial Pain section of Frontiers in Neurology. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by IBSA Institut Biochimique S.A. (Lugano, Switzerland).

ORCID iDs

Pierangelo Geppetti

Silvia Benemei

Valentina Favoni

Cristina Tassorelli

Ilenia Corbelli

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Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized,double-blind,placebo-controlled dose-finding pilot study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Study design and objectives

Ethical considerations

Patient population

Study procedures

Outcome measures

Statistical methods

Results

Demographics

Efficacy

Safety and tolerability

Discussion

Conclusions

Article highlights

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

ORCID iDs

References