Efficacy of a fixed combination of diclofenac 75 mg + thiocolchicoside 4 mg as solution for injection, in relieving back pain symptoms. Controlled study vs. diclofenac 75 mg solution for injection and placebo. RELIEF Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Epifarma S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

30 Mar 2023 → 10 Jun 2025

Decision date (initial)

2025-01-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518753-42-00

EudraCT number

2022-000724-37

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of the study is to demonstrate the superiority of the test fixed combination of diclofenac 75 mg + thiocolchicoside 4 mg given via intramuscular (i.m.)
injection over the reference diclofenac 75 mg i.m. and the superiority of both test and reference over placebo i.m., in relieving pain symptoms in adult patients with
acute moderate-severe low back pain (LBP) after 48 (± 2) hours from the start of treatment (2 i.m. injections on Day 1 and Day 2 of all investigational medicinal
products). Efficacy will be determined by a 100-mm Visual Analogic Scale (VAS) for the assessment of pain.

Secondary objectives 1

1. The secondary objectives of the study are to compare the efficacy of test, reference end placebo groups in: •Pain symptoms (VAS for pain) at all the other daily time points, up to 7 days from the start of treatment, i.e. 5 days after the 2nd i.m. injection; •Proportion of responder patients after 48 hours (Day 3) and 7 days (Day 7) from the start of treatment; •Muscle contracture (Schober index); •Disability due to LBP, as measured using the Roland Morris disability questionnaire; •Consumption of rescue medication (oral diclofenac 50 mg tablet); •Tolerability and safety of the IMPs, assessed through summaries of adverse events, the frequency of discontinuation of treatment due to adverse events, laboratory evaluations, electrocardiograms (ECGs), and vital signs (sitting heart rate, sitting systolic/diastolic blood pressure, respiratory rate, body temperature).

Conditions and MedDRA coding

Low back pain (LBP). LBP is one of the most frequent and disabling health problems. It is estimated that about 80% of adults will experience an episode of acute or chronic LBP at least once during their lifetime The mechanism underlying acute LBP may be disk-, muscle- or posterior articulation related. The aim of the treatment is always to obtain early and maximum relief of the local and regional pain, as well as to improve mobility and physical function.

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1. Male and female patients aged ≥ 18 years; 2. Patients with acute LBP at the moment of initiating treatment; LBP is defined as pain initiating from the area below the tips of the scapulae and above the buttocks, with onset no more than 12 weeks prior to the screening visit; 3. Back pain of moderate to severe intensity, defined as ≥ 50 mm at VAS; 4. Patients with stable muscle contracture; a muscle contracture is defined as an increase < 5 cm in the distance between the two fingers of the examiner in the Schober test performed at the screening visit; 5. If female and of child-bearing potential, the patient must use a highly effective method of birth control during the study treatment period and until one month after the end of treatment. Highly effective birth control methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence; 6. If female and of child-bearing potential, the patient must be non-nursing and should not become pregnant throughout the whole study duration; all females of child-bearing potential must have a negative urine pregnancy test prior the first administration. A childbearing potential female is defined as a fertile female, following menarche and until becoming post-menopausal unless permanently sterile (permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy). A postmenopausal state is defined as no menses for 12 months without an alternative medical cause; 7. Satisfactory general health status as determined by the Investigator based on medical history and physical examination; 8. Patients must understand and provide written informed consent before they can participate in the study. They must understand the study procedures of the trial, and be willing to complete the required assessments.
2. 9. If male patient, the patient must use an effective method of birth control during the study treatment period and until three months after the end of treatment. Effective birth control methods include: permanent sterilization methods (i.e. vasectomy); sexual abstinence; use of condom with spermicide.

Exclusion criteria 2

1. 1. Patients with symptoms that might be attributable to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) at inclusion and in the 48 hours preceding the inclusion in the study or contact with subjects positive to SARS-CoV-2 in the 48 hours preceding the inclusion in the study; 2. Patients with a history of cervical, thoracic, or lumbosacral pain for ≥ 50% of the time in the year prior to screening; 3. Patients with presence of lumbosciatalgia; 4. Patients with a history of any LBP episode, except the current acute episode, within 3 months prior to screening that was associated with disability, or required treatment with an opioid analgesic; 5. Patients with acute LBP caused by a serious or malignant condition; 6. Patients with acute LBP of traumatic origin; 7. Patients with acute LBP of infective origin; 8. Patients with acute LBP caused by a rheumatic disease; 9. Patients on treatment with anticoagulant agents; 10. Patients who underwent spinal surgery in the year prior to screening or had a history of more than one spinal surgery; 11. Patients who had a history of severe lumbar spinal stenosis, fibromyalgia, or ankylosing spondylitis; 12. Patients with a medical history of seizures; 13. Pregnancy or lactation period; 14. Women with childbearing potential who are not using highly effective methods of birth control to avoid pregnancy and who are not willing to use highly effective methods of birth control until one month after the end of the treatment; 15. Women with polymenorrhea; 16. History of alcohol or drug abuse; 17. History of allergy or hypersensitivity or intolerance to diclofenac or thiocolchicoside, and/or to active or inactive excipients of the used IMPs formulations; 18. Known hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs); 19. Use of non-steroid anti-inflammatory drugs (e.g. acetyl salicylic acid) and analgesics (with the exception of diclofenac) in the week before the entry in the study. Chronic intake of small doses of acetylsalicylic acid (≤ 162 mg/daily) taken for at least 30 days prior to the first dose of study medication for non-analgesic reasons may be continued for the duration of the study; 20. Use of diclofenac in the 12 hours preceding entry in the study; 21. Use of any other treatment or medication that can alter the perception of pain (e.g. heparinoids, opioids, psychotropic agents, anti H1 agents or analgesics like glucocorticosteroids, NSAIDs, etc.) for the same indication or other indications (e.g. rheumatoid arthritis) in the week before the entry in the study; 22. Use of diuretic agents in the 30 days preceding entry in the study; 23. History of active or suspected esophageal, gastric, pyloric channel, or duodenal ulceration or bleeding within 30 days preceding screening; 24. History of uncontrolled chronic or acute concomitant disease which, in the Investigator’s opinion, would contraindicate study participation or confound interpretation of the results. In particular, patients with any of the following diseases should be excluded from participation: overt congestive heart failure (NYHA class II-IV), ischemic heart disease, peripheral arterial disease and/or cerebral vascular disease, severe liver or renal impairment, alterations of haematopoiesis; 25. Patients in which the administration of the IMP is contraindicated, such as in case of flaccid paralysis and muscular hypotonia; 26. Participation in any other clinical study or investigation within 30 days prior to the screening or use of any investigational product within a period of more than 5 half-lives, whichever is longer.
2. 27. Males who are not willing to use effective methods of birth control until three months after the end of treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary efficacy endpoint is the sum of pain intensity difference-SPID, from baseline to Day3 (4 measurements every 12hours, 2 morning/2 evening) in VAS for pain score at rest. Pain intensity difference-PID from baseline is calculated for each of the 4 measurements performed up to Day3 (2 measurements in the morning/2 in the evening) by subtracting each pain intensity-PI score from the baseline PI score. The overall SPID is calculated for the evaluation of the primary efficacy endpoint.

Secondary endpoints 7

1. Key secondary efficacy endpoint Changes from baseline to Day 3 and Day 7 of muscle contracture (Schober index).
2. SPID vs. baseline based on morning and evening daily measurements of VAS for pain at all the other daily time points, up to 7 days from the start of treatment, i.e. 5 days after the 2nd i.m. injection.
3. Proportion of responder patients after 48 hours (Day 3) and 7 days (Day 7) from the start of treatment. A responder is defined as a decrease of VAS for pain = 50% vs. baseline (Day 1, pre-administration). Patients who will intake rescue medication within 48 hours from the start of treatment will be considered as non-responder.
4. Changes from baseline to Day 3 and Day 7 of disability due to LBP, as measured using the 24-item Roland Morris disability questionnaire.
5. Use of rescue medication (diclofenac 50 mg tablet): number and percentage of users, number of days with use and number of used tablets, up to Day 3 and up to Day 7.
6. Time elapsed from date/hour of first study drug administration to first intake of the rescue medication.
7. Safety endpoints • Frequency of adverse events and frequency of discontinuation of treatment due to adverse events • Changes from baseline of safety laboratory parameters; • Electrocardiogram (ECG); • Changes from baseline of vital signs (sitting heart rate, systolic/diastolic blood pressure, respiratory rate, body temperature); • Changes from baseline of findings at clinical examination.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Epifarma S.r.l.

Sponsor organisation

Epifarma S.r.l.

Address

Via San Rocco 6

City

Episcopia

Postcode

85033

Country

Italy

Scientific contact point

Organisation

Epifarma S.r.l.

Contact name

Biagio Trupa

Public contact point

Organisation

Epifarma S.r.l.

Contact name

Biagio Trupa

Third parties 5

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 34 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications