STUDY GOALS AND OBJECTIVES

The objective of the study is to compare early progesterone administration and placebo in patients with severe TBI with the following specific aims:

1. Compare the baseline GCS on admission and 15 days after initiation of treatment in both arms of the study.
2. Compare the TNF alpha levels at baseline and 15 days after initiation of treatment in both arms of the study.
3. Determine the GOS 15 after initiation of treatment in both arms of the study.

Determine whether there is a statistically significant difference between both study arms at the end of the study.

 

Study Design

The study is a multicenter, randomized, controlled, single blinded clinical trial.

 

METHODOLOGY

In the period between March and June 2015 30 patients with severe traumatic brain injury were enrolled in this randomized controlled single blinded multicenter study. The clinical, radiological as well as the laboratory assessments were performed on admission and 15 days after the commencement of treatment.

 

Subjects

Inclusion criteria

Eligible patients were adults who had severe TBI with a Glasgow coma Scale (GCS) score of 4 to 9. Patients were enrolled in the study, if the treatment could be initiated within 12 hours after injury.

 

Exclusion criteria

Patients who had sever anoxic brain damage or brain death; history of hormonal therapy before injury; clinically unstable patients (PO2 < 60mmHg, or a systolic blood pressure <90mmHg, or if patients had cardio-pulmonary resuscitation); pregnant and lactating females; or had an associated spinal cord injury, were not included in the study.

Randomization strategy

Patients enrolled in the study were randomized to receive either progesterone or placebo. Randomization was done using a generation of random numbers protocol by the SPSS computer program version 20.0 with closed envelopes with disclosure of the treatment arm after confirming eligibility and exclusion criteria of the patient.  

Informed Consent

Patients were enrolled in the study only after obtaining a written informed consent from legally authorized representatives of the patient, who were informed about inclusion in the study but blinded to the arm to which the patient would be allocated.

Study Interventions

Patients, who were assigned to the progesterone arm, were given hydroxyl-progesterone (Cidolut-Depot 250 mg/1ml) at a dose of (1 mg/kg twice daily by an intramuscular route for 5 consecutive days).

Outcome Measures AND Follow-UP

Primary Outcome Measures

The primary outcome measure is the GCS and TNF alpha on admission and 15 days after admission

Secondary Outcome Measures

The secondary outcome is the assessment of the GOS 15 days after admission and on discharge.

Patients, who were discharged from the hospital, were followed up on an outpatient basis. The post discharge follow-up was mainly clinical; however, no further radiological or laboratory investigations were performed unless an unexpected deterioration in the patient’s clinical condition took place. Patients, who failed to attend follow up at the outpatient department, were contacted by phone to determine whether any deterioration or death took place. In this study the median follow-up period was 6.7 months.

Sample Size

Initially, 33patients were included in this study. However, the relatives of two patients refused to participate in the study, and one patient was transferred to another hospital.

ANALYSIS AND RESULTS

Sample homogeneity:

Demographic data (age and gender) were studied against both study groups (progesterone and placebo) P = 0.506 and 0.925 respectively (P>0.05). This was done using the (T-test for two independent groups and the Kolmogorov-Smirnov "K.S" test) respectively.

The table shows no significant differences between control and study groups, for all variables, before medical treatment, which reflects the homogeneity of the two samples.

Hypotheses

Hypothesis 1

Is to test whether there is a statistical significance between both arms of the study regarding:

a) Glasgow coma scale.

b) Glasgow outcome score.

c) Tumor necrosis factor alpha.

Before and after 15 days of starting progesterone treatment.

H₀:m₀=m₁where m₀ represents GCS, GOS and TNF alpha before treatment, and m₁represents GCS, GOS and TNF alpha 15 days after  treatment.

Hypothesis 2

Is to determine whether any of the variables in the study has a statistically significant effect on neurological outcome of patients included in the study.

H₀: PiÏGi for i=1,2 (1= favorable and 2= non-favorable outcomes). Where P=patients and G=groups.

Efficacy of progesterone group

The following variables showed the following significant changes in the progesterone group:

1-       Temperature: there is a mild increase in average temperature in patients after treatment compared to before treatment, but this remained within the average range.

2-       G.C.S: There is a significant improvement in conscious level after treatment.

3-       Serum TNF alpha: there is a significant decrease in serum TNF alpha level after treatment.

As regards the other variables, there is no significant difference, between values, before and after treatment.

Comparison between Progesterone and Placebo Groups after Medical Treatment

The results of the table above show no significant difference between control and study groups, for all variables under assessment, 14 days after treatment.

The results show no significant difference between both groups, regarding ventilation. Sig = 0.984 (P>0.05)

Tables (3a and 3b) show that, for all variables, there is no statistically significant difference between both groups. Accordingly, progesterone failed to produce a statistically significant improvement in outcome for patients included in this study group.

The Effect of Different Variables on Patient Outcome

The following table shows the most important variables, which have been found to influence the neurological outcome (favorable, and unfavorable), for all patients included in the study. This was done using a stepwise linear binary discriminate function.

The equation shows that the GCS is the single most important variable resulting in a highly significant discriminate function, where the Chi-square test (P-value <0.01), also with an increased value of Canonical correlation and decreased Wilks' Lambda coefficient.

From the above table, it can be found that the ability of the model to predict is excellent, where it succeeded in discriminating 95% of the total observation.

DISCUSSION

Our results indicate no statistically significant difference in GOS or TNF alpha levels (P>0.05) between both groups included in the study.

This shows that, when compared to placebo, progesterone failed to produce a statistically significant improvement in patient outcomes as measured by GOS 14 days after initiation of treatment. This did not change over a median follow up of 6.7 months.

Our results contradict early (published) results [1, 3-5]. In the meantime, they coincide with the results of [6-11].

This discrepancy is created by the fact that the results of early single center studies indicated, that the administration of progesterone in TBI patients was both effective and well tolerated. However, the two most recent, large, phase-III, multicenter, controlled, double-blinded, randomized clinical trials namely, the PROTECT III study and the SYNAPSE study, which enrolled more than 2000 patients, came out with disappointing results, and revealed failure of progesterone to achieve any improvement in the neurological outcome of patients with severe TBI.

The recent poor results of the PROTECT and SYNAPSE trials, for progesterone in TBI, have induced researchers to seek possible causes for the negative outcome, which these two studies have reported. Possible explanatory factors, which have been indicated by researchers include; 1) the patho-physiological complexity of TBI; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. Additionally, other factors, which may have contributed to the negative results include: 1) suboptimal doses and treatment durations in the Phase 2 studies; 2) lack of Phase 2B studies to optimize these variables before initiating Phase 3; and 3) the lack of incorporation of the preclinical and Chinese Phase 2 results, into the Phase 3 designs. Given these circumstances and the exceptional potential of progesterone as a TBI therapeutic, recent studies recommend a return to phase 2B trials [12].

Because progesterone has been proven to be safe and well tolerated in all patients with severe TBI, no adverse effects of progesterone administration have appeared in our study. In this study, the I.M route has been used, to avoid an increased risk of phlebitis or thrombo-phlebitis of I.V use, and fortunately no females, where menstrual disturbances may take place, have been included in the study group.

A small number of patients and lack of long term follow limit our study up. Adherence to the strict inclusion criteria and accurate data collection and analysis have resulted in a small number of patients being enrolled. However, the results, presented in the study, coincide with the most recent published series reported in the literature [6, 8, 10].

Although the remarkable potential neuro-protective effects of progesterone, in TBI, stroke, intracranial hemorrhage, epilepsy and other neurological diseases in all age groups, have been proven more than once in preclinical studies [13-30] clinical trials have failed to reproduce the results obtained in the laboratory setting. The causes behind this discrepancy warrant further investigation [9,12]. Also, as multiple pathways are involved in the secondary cascade of TBI, combination of pharmacological therapies targeting various mechanisms may work better than mono-therapy with progesterone alone. As proven in other studies, progesterone was reported to be more effective in treatment of TBI, when administrated with Vitamin D than progesterone given individually [31, 32].

Progesterone with other chemicals such as nicotinamide, magnesium sulphate, and thyrotropin releasing hormone (TRH) was also investigated on animal models of TBI, and better outcome was observed [33, 34].

CONCLUSION

This study failed to show an improvement in neurological outcome for patients with severe TBI, who received progesterone compared to placebo with a median follow up of 6.7 months. However, the small number of patients, the short period of follow- up and the potential remarkable Neuro-protective benefits of progesterone, which have been proven in a laboratory setting, warrant further studies to find out the reason behind this discrepancy.