Safety and efficacy study of a diclofenac hydroxypropyl β-cyclodextrin (HPßCD) 75 mg subcutaneous (s.c.) and intramuscular (i.m.) formulation as compared to the reference marketed Voltaren® 75 mg i.m. in the treatment of acute moderate to severe pain following minor orthopaedic surgery
| ISRCTN | ISRCTN78851459 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN78851459 |
| Clinical Trials Information System (CTIS) | 2008-000846-30 |
| Protocol serial number | 08I-Dcsc04 |
| Sponsor | Institut Biochimique SA (IBSA) (Italy) |
| Funder | Institut Biochimique SA (IBSA) (Italy) |
- Submission date
- 13/03/2013
- Registration date
- 22/03/2013
- Last edited
- 19/05/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Surgery
Plain English summary of protocol
Background and study aims
Parenteral diclofenac, i.e. diclofenac injection is frequently used to deliver pain relief following minor orthopaedic surgery.
Marketed injectable formulations usually contain 75mg diclofenac sodium in a 3-ml volume and can be administered only intramuscularly (injected directly into a muscle) or intravenously (injected directly into a vein).
IBSA Institut Biochimique has developed a new 1ml volume formulation containing Hydroxypropyl-ß-cyclodextrin (HPßCD), a solubility enhancer to allow subcutaneous (injection in which a needle is inserted just under the skin) administration in addition to intramuscular (i.m.) administration. This study was aimed at assessing the efficacy and safety of Diclofenac HPßCD 75mg administered either subcutaneously or intramuscularly, as compared to the reference product Voltaren® 75mg for i.m. administration.
Who can participate?
The study recruited a total of 325 in-patients, male and female, aged ≥ 18 to ≤ 65 years, with acute moderate to severe pain within 6 hours after a minor orthopaedic surgery (i.e. arthroscopic meniscectomy, arthroscopic removal of bone fragments, surgical correction of hallux valgus).
What does the study involve?
Study patients randomly received a single (s.c. or i.m.) injection of Diclofenac HPßCD 75 mg/1 ml or a single i.m. injection of Voltaren® 75 mg/3 ml administered in the upper part of the gluteus. In case pain was still present, the same treatment was repeated 18-24 hours after the first injection. The overall study duration (for one patient) was 7 ± 2 days.
Local tolerability at injection site was assessed by the investigator up to 18 hours after the first injection, postsurgical pain was evaluated by the patients by means of a 0-100 mm Visual Analogue Scale (VAS) during the 6 hours post-surgery. Blood was taken for evaluation of the general safety of the treatments before the injection and 1 week after surgery/treatment.
What are the possible benefits and risks of participating?
The possible benefits deriving from the participation in the trial, regardless of the treatment received by the patient, were the decrease in pain caused by the orthopaedic surgery.
As diclofenac sodium is a well-known substance in the medical world and treatment lasted for a limited period of one injection (or if needed, for a second injection the following day), the patient participation in the study didn't bring to any particular risk.
The possible side effects were related to active principle, diclofenac sodium.
The most common ones are the side effects affecting the gastro-intestinal apparatus: cramps or abdominal pain, constipation, diarrhoea, indigestion, nausea. More serious cases of bleeding or ulceration (perforation) intestinal walls have less frequently been observed. An increase in the values of the emphatic enzymes may occur, it is usually reversible and rarely leads to a liver disease. Other possible reactions due to administration of diclofenac burden the central nervous system, or cause skin rash and allergic reaction, water retention and swelling, and seldom kidney dysfunction.
The administration of the treatment intramuscularly or subcutaneously might cause local reactions. In previous studies with the same formulation, severe local reactions have rarely been observed, and anyway solved spontaneously within some hours. β-cyclodextrins have no biological activity and if administrated together with diclofenac sodium do not influence its activity. We can thus state that they do not cause any risk to the patients health.
Where is the study run from?
The study was conducted in 25 investigational sites in Italy.
When is the study starting and how long is it expected to run for?
First patient in: September 29, 2008
Last patient out: September 30, 2009.
Who is funding the study?
IBSA Institut Biochimique SA, Via del Piano, CH-6915, Pambio.Noranco (Switzerland)
Who is the main contact?
Prof. Sandro Giannini
Direttore della U.O. VI Divisione di Chirurgia Ortopedico - Traumatologica
IRCCS Istituti Ortopedici Rizzoli
Via Pupilli 1, 40127 Bologna
Italy
Contact information
Scientific
IRCCS Istituti Ortopedici Rizzoli
Via Pupilli 1
Bologna
40127
Italy
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Open-label multicentre randomised parallel group active-controlled design |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Open-label, randomised, controlled, parallel group study for the evaluation of safety and efficacy of DIclofenac HPßCD 75 mg ampoules s.c. in compaRison with DiclofEnaC HPßCD 75 mg ampoules i.m. and Voltaren® 75 mg ampoules i.m. in the treatment of acute moderate to severe pain following minor orThopaedic surgery |
| Study acronym | DIRECT |
| Study objectives | To assess the efficacy and safety of Diclofenac HPßCD 75mg administered either subcutaneously or intramuscularly, as compared to the reference product Voltaren® 75mg for i.m. administration. |
| Ethics approval(s) | The study protocol was reviewed and approved by the Independent Ethics Committee (IEC) of each of the sites involved in the study. The coordinating IEC (IRCCS Istituti Ortopedici Rizzoli di Bologna) approved the protocol on 3 June 2008. |
| Health condition(s) or problem(s) studied | Minor orthopaedic surgery (i.e. arthroscopic meniscectomy, arthroscopic removal of bone fragments, and surgical correction of hallux valgus) |
| Intervention | Patients enrolled in the study were randomised to receive one of the three following Investigational Medicinal Products (IMPs): Group 1: Diclofenac HPßCD 1.0 ml ampoule, s.c. administered Group 2: Diclofenac HPßCD 1.0 ml ampoule, i.m. administered Group 3: Voltaren® 3.0 ml ampoule, i.m. administered All the IMPs were given in single doses. If required by a persisting pain, the IMP administration was repeated on Day 2 (approximately 18-24 hours after the first administration). |
| Intervention type | Drug |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Voltaren® (diclofenac) |
| Primary outcome measure(s) |
Local tolerability (at the injection site), as assessed by the investigators at 10, 30, 60, 90 minutes and at 3, 6 and 12-18 hours after the first IMP administration by scoring any presence of redness, swelling and hardening, by means of 4-point severity scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The mean overall score carried out at any time point represented the primary variable. The overall score range between 0 and 9. |
| Key secondary outcome measure(s) |
Additional safety variables assessed during the study were: |
| Completion date | 30/09/2009 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | All |
| Target sample size at registration | 325 |
| Key inclusion criteria | 1. Adult males and females in-patients aged ≥ 18 to ≤ 65 years 2. Subjects undergoing one of the following minor orthopaedic surgeries: 2.1. Arthroscopic meniscectomy 2.2. Arthroscopic removal of bone fragments 2.3. Surgical correction of hallux valgus 2.4. Presence of moderate to severe post-operative pain, scored as ≥ 40 mm on a 0-100 mm Visual Analogue Scale (VAS) 2.5. Pain starting not more than 6 hours since surgery |
| Key exclusion criteria | 1. Patients with evidence of systemic infection or infection at the site of operation 2. Complications occurring after surgical procedure 3. Patients with clinical signs or a diagnosis of known gastroduodenal ulcer 4. Patients with clinical signs or history of coagulation disorders, or with a history of recurrence ulceration or gastrointestinal (GI) bleeding 5. Patients under chronic treatment with topical or systemic analgesics / Nonsteroidal anti-inflammatory drugs (NSAIDs) 6. Intake of any systemic NSAID or analgesic in the last 12 hours before surgery 7. Opioids in the 7 days before surgery, or corticosteroids (by any administration route) in the 60 days before surgery |
| Date of first enrolment | 29/09/2008 |
| Date of final enrolment | 30/09/2009 |
Locations
Countries of recruitment
- Italy
Study participating centre
40127
Italy
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|---|
| IPD sharing plan summary | Not provided at time of registration |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 20/04/2022 | 19/05/2022 | No | No | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
