Ignite Creation Date:
2025-12-24 @ 11:59 AM
Ignite Modification Date:
2026-01-01 @ 2:23 AM
Study NCT ID:
NCT05935761
Status:
NOT_YET_RECRUITING
Last Update Posted:
2025-11-06
First Post:
2023-06-28
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Investigating Novel Interventions for Low Back Pain in US Military Veterans: A Randomized Controlled Adaptive Phase II Trial
Sponsor:
VA Office of Research and Development
Organization:
Study Overview
Official Title:
Investigating Novel Interventions for Low Back Pain in US Military Veterans: A Randomized Controlled Adaptive Phase II Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2025-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Chronic pain symptoms are very common among U.S. Military Veterans and have a profound negative impact on mental health symptoms and quality of life, in addition to increasing risk for suicidal ideation and suicidal behaviors. There are currently extremely few safe and effective pharmacological treatments for chronic pain disorders, and the clinical need to develop new therapeutics for pain has never been more urgent. Fueled by the worsening opioid crisis and further exacerbated by the COVID-19 pandemic, opioid and other drug overdose deaths have climbed to staggeringly high levels. The rapid development of medications for the management of chronic pain conditions that are safe, well-tolerated, efficacious and non-addicting is thus of paramount importance. The two neurosteroid candidates to be investigated in this trial are naturally occurring molecules enriched in human brain and potentially ideal candidates for safe and effective chronic pain treatment.
Detailed Description:
Pain is one of the most common reasons that Americans seek medical care, with more than 50 million Americans reporting pain that is chronic (CDC NHIS data) and almost 20 million Americans reporting high impact pain that affects major life activities (Nahin, 2015). Chronic pain conditions disproportionately impact U.S. Military Veterans, and back pain is one of the most common diagnoses among Iraq/Afghanistan-era Veterans. The often-debilitating sequelae of chronic low back pain profoundly impacts quality of life and function in a very large number of Veterans and is substantial risk factor for the development or worsening of depression, anxiety and suicidal ideation. Commonly used treatments for pain include long-term opioid use, which is frequently suboptimal and has played a substantial role in the recent surge of opioid-related addiction and deaths. Non-opioid pharmacological interventions that maximize analgesia and minimize adverse outcomes are thus of critical national importance.
Neurosteroids exhibit pleiotropic actions that are highly relevant to central nervous system conditions, including pain disorders. Both preclinical and clinical studies provide strong evidence for the role of neurosteroids in pain. Among other similar studies, the investigators' laboratory has also demonstrated that allopregnanolone levels are reduced in Veterans reporting low back pain and chest pain. Moreover, the recently completed randomized clinical trial (RCT) demonstrated that Veterans randomized to pregnenolone (an endogenous precursor of allopregnanolone) demonstrated significant reduction in low back pain compared to placebo (Naylor et al 2020). The highest dose of pregnenolone resulted in the greatest improvements in pain intensity ratings but the investigators' data suggested that higher doses of this molecule may be even more efficacious. Thus, an RCT to optimize dosing of pregnenolone is warranted. Furthermore, dehydroepiandrosterone (DHEA) is another neurosteroid that has been implicated in pain. The investigators' laboratory (and others) demonstrates that DHEA levels are generally inversely associated with pain and the preliminary data indicate that supplementation with DHEA is associated with a reduction in pain symptoms. Administration of DHEA could thus also represent a novel therapeutic intervention for chronic pain symptoms. The investigators therefore propose to utilize an efficient and informative adaptive trial design to evaluate the efficacy and safety of these two promising molecules for the treatment of chronic low back pain.
Specific Aim 1: To conduct a Phase II adaptive randomized, double-blind, placebo-controlled trial with flexible dosing of pregnenolone, DHEA or placebo (1:1:1 randomization) to highest well-tolerated doses in 108 Veterans with chronic low back pain who served in the U.S. Military. Safety and efficacy will be determined for each chronic low back pain intervention over the course of 4 weeks (total study duration is 6 weeks). Hypothesis 1: Based on the investigators' previously published RCT showing that 500 mg of pregnenolone significantly reduces low back pain, it's hypothesize the investigators will replicate these positive findings with the pregnenolone 500 mg dosing strategy and that pregnenolone at higher doses of 1,000 mg and 2,000 mg per day will result in even greater improvements in low back pain Hypothesis 2: DHEA levels at baseline and post-treatment will predict therapeutic response and higher doses will result in greater improvement in low back pain. Hypothesis 3: Pregnenolone and DHEA will be safe and well-tolerated in this adaptive clinical trial design using flexible dosing.
Specific Aim 2: To conduct biomarker candidate investigations quantifying pregnenolone, DHEA and their neurosteroid metabolite levels (allopregnanolone, others) in serum at baseline, during treatment and post-treatment with pregnenolone and DHEA using highly sensitive and specific mass spectrometry-based methodologies (GC/MS/MS) in order to: a.) characterize the metabolic profile and pharmacokinetics of pregnenolone and DHEA and b.) identify predictors of therapeutic response (potentially yielding valuable dosing information and identifying windows of optimal therapeutic efficacy). Hypothesis: Based on the preliminary candidate biomarker data, the investigators hypothesize that changes in pregnenolone, pregnenolone metabolites, DHEA and DHEA metabolite levels post-treatment will be predictive of therapeutic response and identify optimal therapeutic ranges.
As chronic low back pain conditions significantly impact Veterans, there is an urgent need for the development of pharmacological treatments that are safe, efficacious and non-habit forming. The proposed adaptive platform RCT would thus provide pivotal evidence to optimize treatment in pain disorders for Veterans that could be easily translated to active duty and civilian populations. This RCT thus potentially represents a therapeutic breakthrough for the treatment of pain and may also have the added benefit of mitigating other commonly co-occurring symptoms.
Neurosteroids exhibit pleiotropic actions that are highly relevant to central nervous system conditions, including pain disorders. Both preclinical and clinical studies provide strong evidence for the role of neurosteroids in pain. Among other similar studies, the investigators' laboratory has also demonstrated that allopregnanolone levels are reduced in Veterans reporting low back pain and chest pain. Moreover, the recently completed randomized clinical trial (RCT) demonstrated that Veterans randomized to pregnenolone (an endogenous precursor of allopregnanolone) demonstrated significant reduction in low back pain compared to placebo (Naylor et al 2020). The highest dose of pregnenolone resulted in the greatest improvements in pain intensity ratings but the investigators' data suggested that higher doses of this molecule may be even more efficacious. Thus, an RCT to optimize dosing of pregnenolone is warranted. Furthermore, dehydroepiandrosterone (DHEA) is another neurosteroid that has been implicated in pain. The investigators' laboratory (and others) demonstrates that DHEA levels are generally inversely associated with pain and the preliminary data indicate that supplementation with DHEA is associated with a reduction in pain symptoms. Administration of DHEA could thus also represent a novel therapeutic intervention for chronic pain symptoms. The investigators therefore propose to utilize an efficient and informative adaptive trial design to evaluate the efficacy and safety of these two promising molecules for the treatment of chronic low back pain.
Specific Aim 1: To conduct a Phase II adaptive randomized, double-blind, placebo-controlled trial with flexible dosing of pregnenolone, DHEA or placebo (1:1:1 randomization) to highest well-tolerated doses in 108 Veterans with chronic low back pain who served in the U.S. Military. Safety and efficacy will be determined for each chronic low back pain intervention over the course of 4 weeks (total study duration is 6 weeks). Hypothesis 1: Based on the investigators' previously published RCT showing that 500 mg of pregnenolone significantly reduces low back pain, it's hypothesize the investigators will replicate these positive findings with the pregnenolone 500 mg dosing strategy and that pregnenolone at higher doses of 1,000 mg and 2,000 mg per day will result in even greater improvements in low back pain Hypothesis 2: DHEA levels at baseline and post-treatment will predict therapeutic response and higher doses will result in greater improvement in low back pain. Hypothesis 3: Pregnenolone and DHEA will be safe and well-tolerated in this adaptive clinical trial design using flexible dosing.
Specific Aim 2: To conduct biomarker candidate investigations quantifying pregnenolone, DHEA and their neurosteroid metabolite levels (allopregnanolone, others) in serum at baseline, during treatment and post-treatment with pregnenolone and DHEA using highly sensitive and specific mass spectrometry-based methodologies (GC/MS/MS) in order to: a.) characterize the metabolic profile and pharmacokinetics of pregnenolone and DHEA and b.) identify predictors of therapeutic response (potentially yielding valuable dosing information and identifying windows of optimal therapeutic efficacy). Hypothesis: Based on the preliminary candidate biomarker data, the investigators hypothesize that changes in pregnenolone, pregnenolone metabolites, DHEA and DHEA metabolite levels post-treatment will be predictive of therapeutic response and identify optimal therapeutic ranges.
As chronic low back pain conditions significantly impact Veterans, there is an urgent need for the development of pharmacological treatments that are safe, efficacious and non-habit forming. The proposed adaptive platform RCT would thus provide pivotal evidence to optimize treatment in pain disorders for Veterans that could be easily translated to active duty and civilian populations. This RCT thus potentially represents a therapeutic breakthrough for the treatment of pain and may also have the added benefit of mitigating other commonly co-occurring symptoms.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| I01CX002667-01 | NIH | None | https://reporter.nih.gov/quic… | View |