| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10044755 |
| E.1.2 | Term | Tuberculosis |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary purpose is to investigate the pharmacokinetics of PZA (given for 8 weeks) in a 4-month treatment with higher doses of RIF (35 mg/kg) and PZA (40 mg/kg) and standard treatment of INH (5 mg / kg) and EMB (15-20 mg / kg) compared to standard treatment (RIF 10 mg / kg and PZA 20-30 mg / kg as well as INH and EMB in the above standard doses). |
| Det primära syftet är att undersöka farmakokinetik av PZA (ges under 8 veckor) i en 4 månaders behandling med högre doser av RIF (35 mg/kg) och PZA (40 mg/kg) samt standardbehandling av INH (5 mg/kg) och EMB (15–20 mg/kg) i jämförelse med standardbehandling (RIF 10 mg/kg och PZA 20-30 mg/kg samt INH och EMB i ovan standarddoser). |
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| E.2.2 | Secondary objectives of the trial |
1 The inter-individual variability of drug exposure (AUC0-24h) after the first dose and after two weeks of treatment for high-dose RIF.
2. Cmax for highdose RIF/PZA
3. Comparisons of drug exposure for high-dose PZA and high-dose RIF between day 1 and day 14 on individual level.
4 Is it possible by this high-dose regimen to receive higher drug exposure of PZA than previously proposed thresholds AUC0-24h> 363 mg.h / L and Cmax> 35 mg/L for> 90% of the patients?
5 Characterization of primary PK parameters for high-dose PZA/RIF.
6. The incidence and severity of adverse events (AEs) and SAEs
7. Drug exposure in relation to the bacterial susceptibility level in intervention group and control group with correlation to PK/PD.
8. Description of TBscore during the first 2 treatment months.
9. suPAR during the first 2 months of treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patient> 18 years
2) Confirmed active lung TB by positive culture or positive PCR for the M.tuberculosis complex.
3) Planned to start on active TB treatment (first line) but not yet started treatment.
4) HIV negative
5) BMI> 17
6) Have given written consent.
7) Fertile women should use adequate non-hormonal contraceptives such as a condom and submit to a serum negative pregnancy test if the woman is not postmenopausal. Female patients are not considered fertile if they are post-menopausal, without menstruation for the last 12 months or surgically sterile (bilateral oophorectomy, hysterectomy, tubal ligation 12 months before study start).
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1) Patient >18 år
2) Bekräftad aktiv lung-tbc genom positiv odling alternativt positiv PCR för M.tuberculosis-komplexet.
3) Aktuell för insättning av tuberkulosbehandling (första linjens preparat) men ännu inte påbörjat behandlingen.
4) HIV-negativ
5) BMI >17
6) Har lämnat skriftligt samtycke.
7) Fertila kvinnor ska använda adekvat icke-hormonellt preventivmedel såsom kondom och lämna ett serumnegativt graviditetstest om kvinnan inte är postmenopausal. Kvinnliga patienter anses ej vara fertila om de är post-menopausala utan mens sista 12 månaderna eller kirurgiskt sterila (bilateral ooforektomi, hysterektomi, tubal ligation 12 månader före studiestart).
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| E.4 | Principal exclusion criteria |
1) The research person is not able to give informed consent or is considered so affected by his illness that he or she is unable to understand the study information.
2) Other concurrent infectious disease requiring active treatment.
3) Known hypersensitivity to rifamycin, isoniazid, pyrazinamide, etambutol hydrochloride and / or to any of the excipients listed in section Summary of Product Characteristics or previous serious adverse reaction to RIF, INH, PZA or EMB.
4) Contraindications according to the summary of product characteristics of RIF, INH, PZA or EMB:
• Known hypersensitivity according to exclusion criterion 3 above and severe renal failure (creatinine clearance <30 ml / min) which coincides with exclusion criterion 13 below.
• Previously drug-induced liver inflammation
• Previous acute liver diseases regardless of cause
• Acute liver disease regardless of cause
• Severe liver disease
• Porphyria
• Previously serious adverse reactions when treated with any of the drugs such as drug-induced fever, chills or arthritis
• Concomitant use of drugs whose therapeutic efficacy is very important for the patient whose plasma concentrations are markedly lowered by RIF, and where compensatory dose adjustments to maintain efficacy cannot be made, such as voriconazole, nifedipine, artemeter-lumefantrine and protease inhibitors (see section FASS Interactions)
• Manifest Icterus
• Acute arthritis
5) Treated for active TB in the last year before inclusion.
6) Resistance to any of the drugs (RIF, INH, PZA, EMB) included in standard tbc treatment according to molecular biological or phenotypic resistance assay.
7) Miliary tuberculosis
8) Pulmonary tuberculosis with any of the following:
(a) the presence of copious amounts of acid-fast rods (grade 3) in any of the clinical sputum tests
(b) pulmonary x-ray changes graded to "advanced TB" (according to the National Tuberculosis Association, 1961)
9) Extra-pulmonary tuberculosis without simultaneous pulmonary tuberculosis.
10) Pregnancy and breastfeeding.
11) Immunosuppression (known primary or secondary immunodeficiency including immunosuppressive treatment such as cytostatics, immunomodulatory therapy,> / = 15 mg prednisolone or equivalent cortisone dose)
12) Heart failure fulfilling NYHA Class III or IV
13) Renal failure with estimated GFR <50 mL / min (according to accredited laboratory method)
14) Not well-regulated diabetes mellitus with HbA1c> 62 mmol /mol for type I diabetes and HbA1c> 52 mmol /mol for type II diabetes.
15) Known liver disease including hepatitis and elevated liver transaminases (transaminases> x1.5 of the reference value).
16) Alcohol and / or drug dependence based on patient history.
17) A research person who the investigator after discussing with the study leader, forother reasons than the above, is deemed not suitable for inclusion.
18) Weight <35 kg or> 90 kg at inclusion
19) Patient participated in a clinical trial within 30 days prior to inclusion.
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1) Forskningspersonen som ej bedöms förmögen att lämna informerat samtycke alternativt bedöms så påverkad av sin sjukdom att han eller hon är oförmögen att tillgodogöra sig studieinformationen.
2) Annan samtidig infektionssjukdom som kräver aktiv behandling.
3) Känd överkänslighet mot rifamyciner, isoniazid, pyrazinamid, etambutolhydroklorid och/eller mot något hjälpämne som anges i avsnitt Innehåll i produktresumé eller tidigare allvarlig biverkning mot RIF, INH, PZA eller EMB.
4) Kontraindikationer enligt produktresumé för RIF, INH, PZA eller EMB:
•Känd överkänslighet enligt exklusionskriterium 3 ovan samt allvarlig njursvikt (kreatininclearance < 30 ml/min) som sammanfaller med exklusionskriterium 13 nedan.
•Tidigare läkemedelsinducerad leverinflammation
•Tidigare akuta leversjukdomar oberoende av orsak
•Akut leversjukdom oberoende av orsak
•Svår leversjukdom
•Porfyri
•Tidigare allvarlig biverkan vid behandling med något av läkemedlen såsom läkemedelsinducerad feber, frossa eller artrit
•Samtidig användning av läkemedel vars terapeutiska effekt är mycket viktig för patienten vars plasmakoncentrationer markant sänks av RIF, och där kompensatoriska dosjusteringar för att bibehålla effekten ej kan ske, tex vorikonazol, nifedipin, artemeter-lumefantrin och proteashämmare (se avsnitt Interaktioner i FASS)
•Manifest ikterus
•Akut giktartrit
5) Behandlad för aktiv tbc det senaste året före inklusion.
6) Resistens mot något av läkemedlen (RIF, INH, PZA, EMB) som ingår i standardbehandling för tbc enligt molekylärbiologisk eller fenotypisk resistensbestämning.
7) Miliär tuberkulos
8) Lungtuberkulos med något av följande:
a) förekomst av riklig mängd syrafasta stavar (grad 3) i något av de kliniska sputumproven
b) lungröntgenförändringar som graderas till ”avancerad tbc” (enligt National Tuberculosis Association, 1961)
9) Extrapulmonell tuberkulos utan samtidig pulmonell tuberkulos.
10) Graviditet och amning.
11) Immunsuppression (känd primär eller sekundär immunbrist inkl immunsuppressiv behandling såsom cytostatika, immunmodulerande behandling, >/=15 mg prednisolon eller motsvarande kortisondos)
12) Hjärtsvikt med NYHA klass III eller IV
13) Njursvikt med skattat GFR <50 mL/min (enligt respektive laboratoriums ackrediterade metod)
14) Ej välreglerad diabetes mellitus med HbA1c >62 mmol/mol för typ I diabetes ochHbA1c >52 mmol/mol för typ II diabetes.
15) Känd leversjukdom inklusive hepatit samt förhöjda levervärden (transaminaser >x1,5 av referensvärdet).
16) Alkohol- och/eller drogberoende baserat på anamnestisk bedömning
17) Person som inkluderande läkare efter samråd med studieansvarig av andra skäl än ovan anser ej bör delta i studien
18) Vikt <35 kg eller >90 kg vid inklusion
19) Patient som deltar eller deltagit i en klinisk läkemedelsprövning inom 30 dagar före inklusion.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary variable is the area under concentration and time curve (AUC0-24h) for high dose PZA, in a combination regimen with high dose RIF together with standard doses of INH and EMB, at day 1 after the first dose and at treatment week 2. |
| Primär variabel är arean under koncentration och tidskurva (AUC0-24h) för högdos PZA, i en kombinationsregim med högdos RIF tillsammans med standarddoser av INH och EMB, vid dag 1 efter första dos och vid behandlingsvecka 2. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 and day 14: AUC measured under 24 hours. |
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| E.5.2 | Secondary end point(s) |
1. AUC0-24h for RIF.
2. Cmax for RIF and PZA
3. Primary pharmacokinetic parameters for RIF and PZA
4. Drug exposure in relationship to the susceptibility level of the bacteria (Cmax/MIC and AUC0-24h/MIC).
5. AE and SAE
6. Correlation between TTP and PCR reactivity (Ct value)
7. Description of TB score
8. Description of suPar |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Point 1,2 and 3: are measured under day 1 and day 14.
Point 5: From treatment starts until 4 months for the intervention group and 6 months for the control group.
Point 4 and 6: During the first two weeks.
Point 7 and 8: during the first two months of treatment.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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