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Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the MDR Tuberculosis Pandemic (TBCOX2)

2022年4月7日 更新者：Anne Margarita Dyrhol Riise

Therapeutic Vaccination and Immune Modulation - New Treatment Strategies for the Multidrug-resistant Tuberculosis Pandemic; an Open Label Phase I Clinical Trial of the Therapeutic TB H56:IC31 Vaccine and Cyclooxygenase-inhibitors

Tuberculosis (TB) is a global challenge and for the increasing epidemic of multi-drug resistant (MDR)-TB there is restricted treatment options. This calls for research of new immune-modulating treatment strategies that can strengthen the patients immune system to better fight the TB bacteria. The pro-inflammatory, but still immunosuppressive mediator prostaglandin E2 (PGE2) is produced by cyclooxygenase-2 (COX-2) in inflamed infected tissue. Studies from both human and animal models show that COX-2 inhibitors (COX-2i) can improve the immune system and strengthen vaccines responses.

Hypothesis

  1. A hyperactive COX-2/PGE2 signal system in active TB causes down-regulated immune responses that favour TB survival, but this can be abrogated by COX-2i.
  2. TB-specific immunisation with targeted antigens presented as a therapeutic TB vaccine and enhanced by COX-2i will improve immune-mediated host clearance of TB.
  3. Combinations of COX-2i and a therapeutic TB vaccine to conventional anti-TB chemotherapy offer new treatment modalities for TB, including MDR/XDR-TB.

Approach to test the hypothesis

  1. Study design: 4-arm, open and randomized clinical intervention trial of patients starting treatment for active TB in specialized Norwegian TB centres and where two arms will receive the COX-2i etoricoxib with and without a TB vaccine, one arm vaccine only and the last arm serve as control receiving only standard anti-TB therapy. For safety precautions, only patients bearing sensitive TB strains are included and study arms will be sequentially introduced.
  2. In a mouse model examine in more detail the effects of reversion of chronic inflammation with COX-2i locally in tissue and the interplay with TB vaccine responses, immune regulation, correlates of protection and survival in a well-characterized model for TB-exposed mice.

調査の概要

状態

完了

条件

介入・治療

詳細な説明

The hypothesis is that treating TB patients with a therapeutic TB vaccine and COX-2 inhibiting drugs in addition to standard antibiotic TB therapy will improve the patients immune system and boost TB vaccine responses.

The project will provide safety and immunogenicity data from a Norwegian phase 1 clinical trial of the therapeutic TB vaccine candidate H56:IC31 and the COX-2i etoricoxib given to TB patients together with standard TB antibiotics.

The investigators will also perform exploratory in-depth studies of immune regulatory mechanisms and try to identify biomarkers for efficacy of treatment both in humans and in a parallel mouse model. These results may further optimize the therapeutic strategy and prepare for larger clinical trials and finally contribute to new treatment options for MDR-TB.

Objectives:

  • Study the safety and tolerability of etoricoxib given for 20 weeks (day 0-140) alone and in combination with the therapeutic TB vaccine H56:IC31 given as two immunizations at day 84 and day 140 in patients with active TB disease treated with conventional 26-week anti-TB chemotherapy.
  • Study the immune effects of etoricoxib given for 20 weeks (day 0-140) on immune regulation and TB vaccine (H56:IC31) immunogenicity in patients with active TB disease treated with conventional 26-week anti-TB chemotherapy.

研究の種類

介入

入学 (実際)

39

段階

  • フェーズ 1

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

  • ノルウェー
      • Bergen、ノルウェー、5020
        • Haukeland University Hospital
      • Oslo、ノルウェー、0424
        • Oslo University Hospital

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年～70年 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

Inclusion Criteria:

  1. Age between 18 to 70 years at the time of randomization.
  2. Microbiologically confirmed pulmonary TB (culture and/or PCR + susceptibility testing) and/or microbiologically confirmed extra-pulmonary TB (culture and/or PCR + susceptibility testing).
  3. Drug sensitive Mtb strains (except single resistance where fully adequate anti-TB chemotherapy regimen could be provided).
  4. Is willing and likely to comply with the trial procedures and is prepared to grant authorized persons access to their medical record.
  5. Has completed the written informed consent process prior to the start of screening evaluations.
  6. Females: Ability to avoid pregnancy during the trial.

Subjects may receive H56:IC31 vaccination (arm#2 and #4) if they meet the following criteria:

  1. Sputum obtained prior to 1th immunization (day 84) must be Mtb negative evaluated by at least two consecutive AFS or GeneXpert/PCR at least 7 days apart.
  2. Documented reduction in the extent of TB disease at the infectious site(s) within day 84 evaluated by physical and/or radiological examination.
  3. Clinical improvement with normal vital signs (blood pressure, temperature and pulse), improvement of any TB related symptoms to Grade 1-3, stable or increased body-weight and reduced inflammatory blood parameters (CRP, ESR and WBC counts) compared to baseline.

Exclusion Criteria:

Main exclusion criteria:

(i) Study-specific: Disseminated TB. Evidence of a new acute illness that may compromise the safety of the subject in the trial on study day 0. History of autoimmune disease or immunosuppression. History or laboratory evidence of any possible immunodeficiency state. Anemia (<9 g/100 ml). HIV sero-positivity. Chronic hepatitis B (HBs antigen positive) with increased liver transaminases (ASAT, ALAT) or chronic hepatitis C (HCV RNA positive). Concomitant or sporadic use of NSAID or corticosteroids (>2 times per week). Other immune modulating therapies including DMARDS. Total cholesterol > 7 mmol/L. Hypertension >140/90 mm Hg (treated or untreated) or treated with >1 antihypertensive drug at any blood pressure. Cardiovascular events or stroke in parents, siblings or off-springs occurring < 55 years of age. Serum creatinine above reference levels (females > 90 µmol/L; males > 105 µmol/L). Known diabetes mellitus type I or diabetes mellitus type II with HbA1c >7%. Pregnancy (S-hCG >5 IU/l for females at childbearing age). Breastfeeding.

2. Exclusion criteria for etoricoxib according to SPC: Known hypersensitivity for etoricoxib or etoricoxib tablet substances. Known hypersensitivity for sulphonamides. Active peptic ulcer or gastrointestinal haemorrhage. History of asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic reactions after taking acetyl salicylic acid or NSAID including COX-2 inhibitors. Moderate/severe deranged liver function (Child-Pugh >7). Serum-creatinine clearance < 30 ml/min. Inflammatory bowel disease. Heart failure (NYHA II-IV). Established ischaemic heart disease, peripheral arteriosclerosis and/or cerebrovascular disease, including previous myocardial infarction, angina pectoris, unstable angina, PCI or coronary bypass, previous transitory ischemic attack or apoplexia/stroke.

3. Exclusion criteria for H56:IC31: Known hypersensitivity for vaccines or vaccine adjuvants.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：Arm#1

arm#1 (n=10) receiving etoricoxib from inclusion day 0 and in 140 days.

Step-wise inclusion starting with arm#1,arm#2 and arm#3 (first group) randomized (2:2:1) and if safety data are satisfactory proceeding with arm #4 and the rest of arm#3 randomized (2:2:1).
薬：etoricoxib
cyclooxygenase-2 inhibitor. Anti-inflammatory
他の名前：
  • アルコシア®
実験的：Arm#2
arm#2 (n=10) receiving H56:IC31 vaccine at day 84 and 140 and no etoricoxib.
生物学的：H56:IC31
Therapeutic and prophylactic TB vaccine
介入なし：Arm#3
arm#3 (n=10), the first group (n=5) serving as control to arm#1 and arm#2, the next group (n=5) serving as control to arm#4.
実験的：Arm#4
arm#4 (n=10) receiving etoricoxib from inclusion day 0 and in 140 days and H56:IC31 vaccine at day 84 and 140.
薬：etoricoxib
cyclooxygenase-2 inhibitor. Anti-inflammatory
他の名前：
  • アルコシア®
生物学的：H56:IC31
Therapeutic and prophylactic TB vaccine

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Safety of etoricoxib (arm#1) assessed by the number of participants with adverse events
時間枠：From day 0 until day 238 (14 weeks after the last dose of etoricoxib)
Number and % of study patients with AE or SAE
From day 0 until day 238 (14 weeks after the last dose of etoricoxib)
Safety of H56:IC31 vaccine (arm#2) assessed by the number of participants with adverse events
時間枠：From day 0 until day 238. For vaccine related adverse events; immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Number and % of study patients with AE or SAE
From day 0 until day 238. For vaccine related adverse events; immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Safety of combined etoricoxib and H56:IC31 vaccine (arm#4) assessed by the number of participants with adverse events
時間枠：From day 0 until day 238 (14 weeks after the last dose of etoricoxib). For vaccine related adverse events; from immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Number and % of study patients with AE or SAE
From day 0 until day 238 (14 weeks after the last dose of etoricoxib). For vaccine related adverse events; from immunisation (day 84 and day 140) and 14 days post-immunisation (day 98 and day 154).
Immunogenicity of etoricoxib (arm#1)
時間枠：Day 0 (baseline) to day 84
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
Day 0 (baseline) to day 84
Immunogenicity of H56:IC31 vaccine (arm#2)
時間枠：From before first immunisation (day 84) to 14 days after second immunisation (day 154).
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
From before first immunisation (day 84) to 14 days after second immunisation (day 154).
Immunogenicity of combined etoricoxib and H56:IC31 vaccine (arm#4)
時間枠：From before first immunisation (day 84) to 14 days after second immunisation (day 154).
Total CD4+ T cell cytokine (IFN-γ, IL-2, TNF-α) responses to sum TB peptides.
From before first immunisation (day 84) to 14 days after second immunisation (day 154).

二次結果の測定

結果測定
メジャーの説明
時間枠
Exploratory immune studies
時間枠：From day 0 (baseline) until day 238 (study end); 14, 28, 56, 84, 98, 140, 154, 182, 210, 238 days from baseline (selected timepoints for various analysis).
Study in depth the effect of etoricoxib on immune activation, regulation and TB vaccine immunogenicity measured by the percentage of innate cells (monocytes/MDSC) and CD4+ and CD8+ T cells expressing various activation, supression and regulation markers in response to stimulation with TB antigenic peptide pools (Ag85B, ESAT-6, Rv2660c). Serologi to H56 and gene signature analyses.
From day 0 (baseline) until day 238 (study end); 14, 28, 56, 84, 98, 140, 154, 182, 210, 238 days from baseline (selected timepoints for various analysis).

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Anne Margarita Dyrhol Riise

協力者

University of Oslo
Haukeland University Hospital
Statens Serum Institut

捜査官

  • 主任研究者：Anne Margarita Dyrhol-Riise, PhD、Oslo University Hospital

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2015年11月1日

一次修了 (実際)

2019年9月1日

研究の完了 (実際)

2020年3月23日

試験登録日

最初に提出

2015年7月10日

QC基準を満たした最初の提出物

2015年7月20日

最初の投稿 (見積もり)

2015年7月21日

学習記録の更新

投稿された最後の更新 (実際)

2022年4月8日

QC基準を満たした最後の更新が送信されました

2022年4月7日

最終確認日

2022年4月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • 2015/692
  • 2014-004986-26 (EudraCT番号)

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

はい

IPD プランの説明

The study is published. https://doi.org/10.1038/s41467-021-27029-6

IPD 共有時間枠

Data available as supplementary information in the published manuscript.

IPD 共有アクセス基準

The full source datasets generated during and/or analyzed during the current study are available in the repository of the open science framework (https://osf.io/khvf4)

IPD 共有サポート情報タイプ

  • 研究プロトコル
  • 統計分析計画 (SAP)
  • 分析コード

医薬品およびデバイス情報、研究文書

米国FDA規制医薬品の研究

いいえ

米国FDA規制機器製品の研究

いいえ

米国で製造され、米国から輸出された製品。

いいえ

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