Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): a study protocol for a randomised controlled trial

The aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen®) in the treatment of post-dural puncture syndrome for patients who received neuraxial anaesthesia during childbirth.

Our working hypothesis is that a single intravenous infusion of tetracosactide may avoid the need for the epidural blood patch. To challenge this hypothesis two groups will be compared: the study group receiving an infusion of 1 mg of tetracosactide and the control group receiving a placebo (0.9% saline). Both groups receive standard analgesic treatment and epidural blood patch if needed (after a minimum of 24 h following the injection of the experimental treatment).

The study is a randomised, double-blind, placebo-controlled, parallel-arm, double-centre trial. It is conducted in two different sites, and both sites are part of the same French university hospital. We followed the SPIRIT checklist (Additional file 1). Patient enrolment started in October 2016 and was expected to be completed within 2 years after the start of the study. However, as explained in section 1.3.11. this did not happen.

Once participants are enrolled in the study with informed consent, they are randomised into the two study arms. The study group receives 1 mg of tetracosactide intravenously whereas the control group receives 0.9% saline. Outcomes will be measured between 2 and 6 h, on day 1, day 2, day 3, and between days 13 and 17 post-randomisation. Adverse events are collected throughout the study.

The primary endpoint of the study is the rate of epidural blood patch within a 15-day follow-up period, that is, the number of patients who receive a blood patch within the 15-day period divided by the total number of participants included.

The secondary endpoints are as follows:

The anaesthesiologist checks the patient’s inclusion criteria and the absence of exclusion criteria. After signing of the informed consent, patients are randomised online using the ClinSight-Online software program (Ennov society, Paris, France). The randomisation list was compiled by a statistician, entered into the software and communicated to the pharmacist to prepare the numbered treatment kits. The randomization is performed by block stratification according to site. Patients are allocated to a treatment number (by the ClinSight software). The study is performed double-blinded; both patients and the medical team are blinded to treatment allocation. An anaesthetic nurse prepares the treatment according to the assigned number to which the rest of the healthcare team is blinded. Patient data are collected on electronic case report forms (eCRFs). The sponsor will independently monitor both locations of this multisite trial every ten patients. This data monitoring is performed by a clinical research associate (CRA). His/her role is to check the consent form, the quality of data collection (missing data, data entry errors …), the availability of treatment at each site, the pharmacy process, and the declaration of any serious adverse event. He/she is employed by the sponsor but is independent of the investigators and is not involved in carrying out the study or interpretation of the results. Anonymized data are only accessible to the investigators, the sponsor, and other authorized persons (statistician, data manager …). They will be stored confidentially for 15 years by the sponsor. They will not be used for further studies without further patient agreement. At the end of the study, we plan to communicate trial results to participants, healthcare professionals and the public via a peer-reviewed publication. Authors will be considered in the case of a substantial contribution to the conception or design of the study or the acquisition, analysis or interpretation of data. They will need to have drafted the work or revised it critically. They will all approve the final version to be published. We do not expect the participation of a professional writer. Data not disclosed in the publication will not be accessible.

During the post-partum period, patients are usually followed by midwives. In case of headache, whether an accidental dural puncture is diagnosed or not, the anaesthesiologist is informed by the midwives. Therefore, any symptomatic patient is examined by an anaesthesiologist. The study investigators are the anaesthesiologists working in the maternity department of the two centres.

Patients are enrolled when diagnosed with PDPH based on the anaesthesiologist’s clinical evaluation. They are randomised to receive intravenous tetracosactide or placebo. In the study group, patients receive a single intravenous injection of 1 mg tetracosactide (Synacthen®, Sigma-Tau laboratory, Roma, Italy). Four vials containing 0.25 mg tetracosactide (in 1 ml of solvent) are reconstituted in 100 ml of normal saline (0.9% NaCl). This solution is infused intravenously over 20 min. In the control group, patients receive an equal volume of normal saline: 104 ml over 20 min. The whole intervention is administered over a 20-min course and therefore is not modifiable once begun except for the occurrence of a side effect. A side effect is defined herein as any new abnormality observed upon clinical examination, occurring during the injection. In this case, the treatment is immediately stopped but monitoring and data collection continues.

Standard analgesic medication, as concomitant treatments, is also initiated in both groups from the beginning of headache, as follows:

These treatments are adjusted daily.

The primary and secondary endpoint, including tolerance criteria, are evaluated blinded during infusion of the study treatment, 2–6 h later, 1 day, 2 days, 3 days and between 13 and 17 days post-treatment by the investigator. The latter is conducted by phone call in order to increase the complete follow-up. The total duration of the study is therefore 13 to 17 days. Any alternative analgesic intervention required after receiving the study treatment is reported at each time point as indicated above. The study timeline is summarised in Fig. 2.

Epidural blood patch is performed for patients who reported a persistent moderate to severe headache a minimum of 24 h after administration of the study treatment and 36 h after the dural puncture, based on the clinical appreciation of the anaesthesiologist. Epidural blood patch can be repeated twice if required (i.e., if the headache does not improve or if it increases again). The anaesthesiologist performs the epidural blood patch. Autologous blood is injected into the epidural space using an 18-gauge Tuohy needle. The injection is stopped when the patient feels pressure in the lower back or pain.

Unblinding occurs at the end of the study and once the database has been frozen. Analyses will be carried out on an intention-to-treat (ITT) basis. If data are missing from visits, we will carry forward the last value for which the pain (and other symptoms) has not improved. This is the most pessimistic scenario for this condition, which usually improves spontaneously. Blood patch can only be performed at the hospital, and it is therefore very unlikely that there will be missing data regarding the primary endpoint. If a patient does not receive full treatment, she will be included in the group to which she was randomised for further ITT analysis. Statistical analyses will be performed using IBM SPSS statistics for windows (IBM corp., Armonk, NY, USA) and R (R Foundation for Statistical Computing, Vienna, Austria). All data will be checked for normal distribution using the Kolmogorov test. For normally distributed data, variables will be presented as mean ± standard deviation (SD). Non-normally distributed data will be presented as the median and interquartile range [IQR]. Categorical variables will be presented as number and percentage of the total. To compare the two groups (tetracosactide and placebo), we will use Fisher’s exact test for qualitative data and the non-parametric Mann-Whitney tests for quantitative variables. A comparison of the two groups at randomisation will identify potential bias due to unequal allocation. A multivariate logistic regression analysis will be performed to study factors independently associated with the response to tetracosactide and to control potential confounding factors.

This trial is conducted in accordance with the protocol and in compliance with the moral, ethical and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). It is also conducted in accordance with French legislation (Public Health Code; Act No. 2004–806 of 9 August 2004). It is registered in the Clinical Trial Protocol Registration and Results System: NCT02813655 (registration date: 24 June 2016). An ethics committee (Comité de Protection des Personnes sud Est V, CPP) has approved the study for both participating sites on 6 April 2016. The national drugs authority (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) authorised this trial (authorisation date: 18 April 2016).

During the study period, adverse events will be reported and recorded in the participants’ CRF. Adverse events include any new abnormality observed upon clinical examination, occurring during the study treatment injection or the follow-up period, or any allergic reaction to the treatment. The severity of adverse events will be graded as mild, moderate, severe, life threatening, or death, and the potential relationship between the adverse event and the study treatment will be assessed by clinical judgment. If an adverse event requiring hospitalisation extension or causing a medically critical situation occurs, the event will be recorded as a severe adverse event. All severe and life threatening adverse events or death will be reported to the investigator and to the sponsor within 24 h after the information has been collected. The sponsor will report all such events to legal authorities (ANSM and CPP). The investigator must follow patients until the adverse event has been resolved. All adverse events collected will be described in the trial publication. A severe adverse event is the only reason for unblinding participants and providers before the end of the study. It will be performed by the poison control centre (Anti-poison Centre) which is independent of the study and is the only party with access to the randomisation list.

Because patient enrolment/inclusion was more difficult than expected, the protocol was amended (January 2017) to extend inclusion from PDPH due to a dural puncture carried out by large Tuohy needle to all postpartum PDPH, i.e. PDPH related to a large dural puncture and PDPH related to small needle (25-27G) for spinal anaesthesia. For this reason, a second amendment (November 2018) extended the inclusion period until October 10, 2021.