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Phase 2: Modulation of Gut Microbiota With NBT-NM108 as an Early Treatment for Suspected or Confirmed Symptomatic COVID-19 Patients

This open-label, randomized, and controlled clinical trial aims to determine the feasibility and effectiveness of using NBT-NM108, a novel botanical-based fixed-combination drug, to modulate the gut microbiota and treat early-stage suspected or confirmed symptomatic COVID-19 patients.

  • Planned Enrollment: 44 participants

  • Starting date: 11/2021

  • Ending date: 12/2022

FDA Regulatory Channel

Taken in the form of drinks four times a day (before each main meal and 2 hours after dinner) for 28 days. Each drink is prepared by mixing one sachet (30 g) with 500 ml of water. FDA botanical drug IND

Outcomes

Primary outcome: Gut Microbiota Composition [ Time Frame: Day 0 to 56 ]


Secondary outcomes:

  • Discontinuation of home isolation status

  • Hospitalization status

  • Deaths

Phase 4: An Investigator Initiated Open-label Study Evaluating the Efficacy and Tolerability of Application of Bodewell Products for the Treatment of Atopic Dermatitis

  • Estimated Enrollment: 15 participants

  • Starting Date: 01/2024

  • Ending Date: 09/2025

FDA Regulatory Channel

Bodewell is a non-prescription and contains 22 botanical ingredients in addition to colloidal oatmeal.

Outcomes

Primary outcome: Mean Percentage improvement in Patient Global Assessment (PGA) [ Time Frame: Baseline to week 12 ]


Secondary outcomes: Percent improvement in Dermatology Life Quality Index (DLQI) [ Time Frame: Baseline to week 12 ]

Phase 2: Safety, Tolerability, and Early Efficacy of Oral E-B-FAHF-2 in Subjects With Mild-To-Moderate Crohn's Disease

A randomized, double blind, placebo controlled, parallel assignment phase 2 trial to evaluate the Safety and Tolerability for mild-to-moderate Crohn's Disease (CD) patients over 8 weeks. This is followed by an open-labeled exploratory efficacy extension phase for 6 months.

  • Planned enroll: 28

  • Start Date: 02/15/2023

  • Estimated Completion Date: 05/2025

Regulatory Channel

EBFAHF-2 is a 0.55g capsule that is easy to swallow. The quality, safety and consistency of EBFAHF-2 are established per FDA guidance under a botanical drug title. Low dose (maximum of 2 capsules bid) and full dose (maximum of 5 capsules bid). Weight based dosing will ensure an equivalent amount is given to each individual.


Low dose EBFAHF-2 (29 mg/kg/d divided two times a day) for 2 weeks followed by a full dose (71mg/kg/d divided two times a day) for 6 weeks

Outcomes

Primary Outcomes: Number of grades of adverse events [ Time Frame: 8 months ]


Secondary Outcomes: 

  • Number of participants requiring an escalation in therapy. [ Time Frame: 6 months ]

  • Fecal Calprotectin [ Time Frame: 6 months ]

  • PROMIS Profile 29 [ Time Frame: 6 months ]

  • Self Efficacy Scale: IBDSES [ Time Frame: 6 months ]

  • Immunologic Changes in PBMC cytokine levels [ Time Frame: 6 months ]

Phase 3: Safety and Efficacy of T89 in the Prevention and Treatment of Adults With Acute Mountain Sickness (AMS)

Previous clinical studies showed T89 has substantial benefits in the prevention or amelioration of symptoms associated with acute mountain sickness (AMS).This is double-blind, randomized, placebo controlled pivotal phase 3 study. After informed consent is obtained, eligible subjects will be randomized to one of the 3 study groups (T89 high dose, T89 low dose and placebo control). The study drug will be given orally for 5 days (2 days at sea level and 3 days at high altitude). The clinical assessment of Lake Louise Scoring System (LLSS), blood oxygen saturation, the exercise tolerance, blood pressure and heart rate will be performed at sea level and altitude. A total of 846 subjects will be enrolled with 282 subjects in each treatment arm, and a minimum of 756 subjects are expected to complete the study.

  • Planned Enrollment: 846 participants

  • Starting Date: 07/21/2021

  • Ending Date: 04/2024

Regulatory Channel

T89 capsule is a modernized industrialized version of a traditional Chinese herbal medicine, containing 75mg active substance which is the water extract of Danshen and Sanqi.

Outcomes

Primary outcomes: Change of baseline corrected mean LLSS score on Day 4 morning (next mornings after arrival at high altitude) between T89 and placebo groups. [ Time Frame: Baseline and day 4 ]


Secondary outcomes; 

  • The change of blood oxygen saturation levels (SpO2) at high altitude between T89 and placebo groups. [ Time Frame: Baseline and days 3-6 ]

  • The change of the area under the curve (AUC) of baseline corrected LLSS score-time profile between T89 and placebo groups. [ Time Frame: Baseline and days 3-6 ]

  • The change in total incidence of LLSS score ≥5 on Day 4 morning between T89 and placebo groups. [ Time Frame: Day 4 morning ]

  • The change of percentage reduction of the daily total LLSS score from Day 4 to Day 5 between T89 and placebo groups. [ Time Frame: Days 4-5 ]

  • he change of baseline corrected LLSS score at any given time points between T89 and placebo groups. [ Time Frame: Baseline and days 3-6 ]

Phase 2: Botanical Tincture for Symptoms of Irritable Bowel Syndrome Constipation Predominant (IBS-C) Diagnosed on ROME IV Criteria

The main purpose of this study is to investigate the feasibility of a follow-up larger RCT on the efficacy of Botanical Tincture to relieve abdominal pain in people with Irritable Bowel Syndrome Constipation Predominant (IBS-C).

  • Planned Enrollment: 60 participants

  • Starting Date: Dec 2023

  • Ending Date: Jan 2025

Regulatory Channel

herb tincture at 12ml/dose daily, under FDA Botanical Drug IND category

Outcomes

  • Abdominal Pain Intensity: weekly average of worst daily (in past 24 hours) abdominal pain score scale of 0 (No pain) -10 (Worst imaginable pain) [ Time Frame: 12 week study ]

  • Abdominal Bloating Intensity: weekly average of worst daily (in past 24 hours) abdominal bloating rating on a scale of 0 (absent) - 4 (very severe) [ Time Frame: 12 week study ]

  • Bowel movement frequency: Number of Complete Spontaneous Bowel Movements (CSBMs) each week [ Time Frame: 12 week study ]

Phase 1: Efficacy of a Botanical Supplement to Provide Period Relief

In this study, two products that are used to alleviate period pain will be examined. One test product is botanically based, and the other is a traditional over-the-counter pain reliever with additional components added to support less painful periods. The trial will be a cross-over trial where participants will use the botanical product before, during, and after their first period. Participants will use the botanical product alongside a traditional over-the-counter period product during their second period. Participants will answer surveys and have blood drawn at a third-party lab to answer the main objectives of this trial.

  • Planned Enrollment: 100 participants

  • Starting Date: 02/8/2023

  • Ending Date: 07/01/2023

Regulatory Channel

Participants will take 450mg of Pamprin Botanicals two days before their predicted period and then take it every day during their period. Under the US FDA botanical drug IND

Outcomes

Primary outcome: Changes in common menstrual cycle symptoms [Time Frame: 2 menstrual cycles (approximately 60 days)] [ Time Frame: 60 days ]


Secondary outcomes: Changes in blood biomarkers during the menstrual cycle [Time Frame: 2 menstrual cycles (approximately 60 days)] [ Time Frame: 60 days ]

Phase 2: Investigating The Combination Of YIV-906 And Sorafenib (Nexavar®) In HBV (+) Patients With Advanced Hepatocellular Carcinoma

The aim of this study is to compare the efficacy and safety of YIV-906 plus standard-of-care sorafenib versus those of sorafenib alone as a first-line systemic treatment for patients with Hepatitis B (+) associated advanced hepatocellular carcinoma. YIV-906 (PHY906, KD018) is an immune system modulator. Clinical and preclinical research suggests that YIV-906 could act to enhance the body's immune response to fight cancer and increase the anti-tumor activity of sorafenib and protect and repair the gastrointestinal tract by reducing inflammation and promoting tissue regeneration. Patients in the study arm will be treated orally each 28-day course with YIV-906 (600 mg (3 capsules) BID) + sorafenib (400 mg BID) according to the following schedule: sorafenib BID daily treatment for 28 days, and YIV-906 BID 4 days on and 3 days off weekly in each course. All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 5.0 (CTCAE). The Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be used to establish disease response or progression. The RECIST 1.1 and mRECIST will be used in a blinded independent central review (BICR) to determine the study endpoints. Patients will be evaluated for PFS, TTP, OS, antitumor response every two cycles, and QoL and safety at the beginning of each cycle. Biomarkers are mandatory and will be studied prior to drug administration on day 1 of each cycle. TCM Syndrome Research is optional. PK is only applicable in China study sites and limited to the first 15 male and 15 female patients. Patients will be randomized to either the study drug arm or the placebo arm (2:1 ratio). PK studied immediately prior to dose administration and at 1 hour, 2 hours, 4 hours, and 12 hours post-dose administration on Day 1 of Cycles 1.

  • Planned Enrollment: 125 participants

  • Starting Date: 01/10/2020

  • Ending Date: 12/31/2023

Regulatory Channel

YIV-906 is a botanical drug candidate, composed of an extract of four herbs and administered in oral capsule form.

Outcomes

Primary Outcomes: Progression free survival (PFS) [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months.


Secondary Outcomes: 

  • Time to progression (TTP) [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]TTP is defined as the period elapsing between the date of randomization and the date of disease progression.

  • Overall survival (OS) [ Time Frame: at randomization, then at the end of every two cycle (i.e. approximately every 8 weeks), until death from any cause. Assessed up to 24 months. ]OS is defined as the interval between time of randomization and the date of death from any cause.

  • Objective response rate (ORR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]The Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) will be used to establish disease response or progression

  • Disease control rate (DCR) in each arm [ Time Frame: At baseline, then at the end of every two cycle (i.e. approximately every 8 weeks), until disease progression or discontinuation from study. Assessed up to 24 months. ]DCR will be defined as the proportion of patients achieving either partial response (PR) or complete response (CR) or stable disease (SD).

  • The safety and tolerability of the combination of YIV-906 plus sorafenib as measured by the rate and severity of AEs [ Time Frame: Continuously throughout the study until 28 days after treatment discontinuation ]All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 5.0 (CTCAE).

  • Change of quality of life (QoL) in each arm with HCC18 [ Time Frame: At the beginning of every course (4 weeks) until the end of study. Assessed up to 24 months. ]Each of the domains in the HCC18 will be scored per the assessment's scoring algorithm and summarized using descriptive statistics at baseline

Highlighted IND Trials


FDA Botanical Drug Development Guidance for Industry
 Summary
Definition of "Botanicals":
  • ​Includes plant materials, algae, macroscopic fungi, and combinations thereof.
  • ​Excludes:
    • Animal or mineral components (except as minor components in traditional preparations).
    • Genetically modified botanical species (for single molecular entity production).
    • Products produced by fermentation to create single molecular entities.
    • Highly purified or chemically modified substances from natural sources

Regulatory Approaches
  • OTC Drug Monographs: Botanical drugs with a history of use may be considered for inclusion in OTC drug monographs, but this requires meeting safety and effectiveness standards and inclusion in a USP-NF monograph or a proposal for one. "To be included in an OTC drug monograph, a botanical drug substance must be recognized as safe and effective based on the standards for safety and effectiveness set forth in 21 CFR 330.10(a)(4)."
  • New Drug Applications (NDAs): Botanical drugs can be marketed under an NDA for prescription or OTC use, following FDA approval. Ensuring "therapeutic consistency" is a major issue given the variability of these drugs.
  • This is done through a "totality of the evidence approach" which includes:
    • Botanical raw material control (e.g., agricultural practice and collection).
    • Quality control by chemical test(s) and manufacturing control (e.g., process validation).
    • Biological assay and clinical data.

Botanical Drug Development Under INDs
  • IND Requirement: Clinical investigations on humans must be conducted under an IND unless an exemption applies. Sponsors are encouraged to consult with the FDA if they are unsure if an IND is required.
  • Pre-Submission Consultation: Pre-IND and end-of-phase consultations are "strongly encouraged" to assess information adequacy, address protocol design, and discuss development plans.
  • IND Content: INDs must show the drug is safe for human testing and that the clinical protocol is appropriate. Special considerations for botanicals:
    • Heterogeneity and poorly defined chemical constituents and biological activities are common in botanicals.
    • Previous human use can inform safety, but also requires robust documentation.
    • Stepwise approach to development recommended, with CMC data and early study results used to design later studies. Bridging studies may be needed if material or manufacturing changes occur.

INDs for Phase 1 and Phase 2 Clinical Studies
  • Flexibility Based on Risk: The amount of information needed for an IND is related to prior human experience, known risks, and the phase of drug development. Less CMC and toxicology data is needed for early studies using well-established dietary supplements. However, "gathering of CMC data should be initiated during these phases because such preliminary information should be submitted prior to initiating Phase 3 studies."
  • Stepwise Approach: Clinical development should be a step-wise process, using raw material controls, analytical characterization data and early results to inform the design of later studies.
  • Botanical Raw Material Description:
    • Detailed taxonomic information and plant parts used.
    • Common names in English and other relevant languages.
    • Known active or chemical constituents.
    • "Trained personnel should identify the plant species, plant parts, alga, or macroscopic fungus used via methods including organoleptic, macroscopic, and microscopic examination" and compared to a "voucher specimen".
  • Prior Human Experience: Extensive data should be submitted on prior human use including safety data, sales volume, adverse effects, and references from compendia and traditional medicine sources. "Any literature that is submitted should be provided in English (and in its original language, if other than English)." The relevance to the proposed use needs to be justified.
  • CMC Requirements:
    • Botanical Raw Materials: Identification, authenticity, endangerment status, supplier details, harvest location and conditions, post-harvest processing (drying, grinding etc), control of contaminants, tests for impurities, residual pesticides, microbial limits, toxins, and adulterants.
    • Botanical Drug Substance: Qualitative and quantitative description, manufacturing process, quality control test for appearance, strength, identification of constituents, quantification of constituents, biological assay if active constituents are unknown, mass balance and tests for pesticides, elemental impurities, microbial limits, toxins, stability.
    • Botanical Drug Product: Qualitative and quantitative description, manufacturer analysis, stability data to cover duration of clinical study.
    • Placebo: A placebo should not contain pharmacological activity and while not identical, should be as similar as possible to the active drug.
  • Nonclinical Pharmacology/Toxicology: The extent of nonclinical work depends on human experience. Existing literature must be reviewed and if more exposure is anticipated, additional studies are required. For new botanicals without prior use, a full safety profile similar to non-botanical drugs is needed.
  • Clinical Pharmacology: Pharmacokinetic and pharmacodynamic data are helpful, but if active constituents aren't known then a clinical endpoint may be used.
  • Clinical Considerations: Early-phase clinical studies are generally the same as for synthetic drugs. Well-controlled studies are encouraged early on to examine therapeutic effects.

INDs for Phase 3 Clinical Studies
  • Late-Phase Focus: Continued characterization of the botanical drug, further toxicological data, and the impact of batch variations are key. "Given the more extensive exposure in late-phase clinical studies, additional toxicology data are warranted to support safe human use and facilitate the design of clinical safety evaluations."
  • Batch Variations: Impact of batch variations on therapeutic effect needs evaluation through multiple batch studies.
  • Bridging Studies: Needed when sources, manufacturing or drug substance have changed during development.
  • CMC:
    • Raw Material: Selection of representative raw material batches from three or more cultivation sites. Characterization of raw materials with spectroscopic/chromatographic methods.
    • Drug Substance and Product: Establish specifications, pharmaceutical development should be advanced. A robust manufacturing process for the drug substance and drug product should be established.
  • Nonclinical Safety: Standard animal toxicology studies are required for Phase 3, including:
    • General pharmacology/toxicology (doses in toxicology studies should be high enough to produce measurable toxicity)
    • Pharmacokinetic/toxicokinetic studies (monitoring of key chemical constituents and their metabolic fates)
    • Reproductive toxicology
    • Genotoxicity
    • Carcinogenicity (often needed for chronic use)
    • Other specialized studies.
  • Clinical Pharmacology: Rationale for dose selection.
  • Clinical Considerations:
    • Multiple Batch Analysis: Studies should assess batch effects on clinical outcomes, with randomization to batches and models for analysis to see "if variations observed in botanical drug substance batches do not cause any meaningful differences in the therapeutic effect."
    • Dose-Response: Studies are important to explore optimal dose ranges.
    • Serious Conditions: "Add-on" designs are preferred over stand alone controls for serious conditions, given ethical concerns for using a botanical drug alone with unknown efficacy.
    • Traditional Practices: Incorporation of traditional practices (e.g., selection by traditional criteria) may be acceptable if it enhances therapeutic effects and can be translated for U.S. labeling.
  • Combination Drug Rules: Fixed dose combination rules may or may not apply to multi-botanical products. FDA is considering waivers when there is prior human experience of use of that specific combination.

NDAs for Botanical Drug Products
  • Pre-NDA Meeting: Very important to discuss botanical-specific issues and plan the NDA content.
  • Submission Requirements: Same as other drugs, in eCTD format.
  • Product Description & Prior Use: All IND info must be resubmitted along with any updated data.
  • Quality Control: Starts with the raw material and described in the NDA. GACP procedures must be referenced (WHO, EMA).
    • Identity: Chemical characterization and biological assay (where needed) to establish identity.
    • Chemical Characterization: Full description of analytical methods and mass balance of components.
    • Manufacturing: Complete manufacturing information for drug substance and drug product, process should be finalized.
    • Biological Assay: If needed, biological assays for potency and activity, using reference standards are required. "The batch potency and activity should be measured relative to a suitable reference standard or material; results should be expressed in units of activity calibrated against the reference standard or material."
    • Specifications: Should be clinically relevant. Mass balance tests of botanical drug substance should be evaluated alongside biological assay.
    • Stability: Validated stability methods and stress testing. Re-test periods and expiration dates should be provided.
    • Drug Master File: CMC information can be submitted in a DMF.
    • Naming: Should contact USAN for an established name.
    • Environmental Assessment: An EA will often be needed for wild-harvested botanicals.
  • Nonclinical Safety: Same as non-botanical drugs.
  • Clinical Pharmacology: Bioavailability data are needed, though may use a biological assay if standard pharmacokinetic methods are not possible. Waivers can be given if justified.
  • Therapeutic Consistency: Must show consistency of marketed batches with those used in Phase 3 trials, looking at raw material controls, chemical testing, manufacturing controls, biological assay, and clinical data.
    • Clinical Data: Multiple batch and dose response studies can help show this.
  • Post-Marketing Changes: Changes to raw material sources or manufacturing processes must be assessed to see if batches produced after these changes are similar.
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