| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Fatigue Syndrome/ Myalgic Encephalopathy, as defined by Canadian Consensus Criteria (2003) |
| Myalgisk Encefalopati/Kronisk Utmattelsessyndrom etter kanadiske kriterier fra 2003. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Fatigue Syndrom (ME/CFS) |
| Kronisk utmattelsessyndrom (ME/CFS) |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008874 |
| E.1.2 | Term | Chronic fatigue syndrome |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
|
| 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 objective of this trial is to evaluate the efficacy, toxicity and feasibility of six infusions cyclophosphamide given four weeks apart, for patients with chronic fatigue syndrome (ME/CFS). |
| Hovedhensikten med studien er å evaluere effekt, bivirkninger, og gjennomførbarhet ved seks infusjoner cyclofosfamid gitt hver fjerde uke, til pasienter med kronisk utmattelsessyndrom (ME/CFS). |
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| E.2.2 | Secondary objectives of the trial |
| see secondary endpoints |
| se sekundære endepunkt |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Patients with chronic fatigue syndrome according to Canadian inclusion criteria (2003).
-Duration of disease at least 24 months.
-Severe, moderate/severe, moderate and moderate/mild ME/CFS may be included.
-Age 18-65 years.
-Signed informed consent.
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-Pasienter med ME/CFS etter Kanadiske inklusjonskriterier (2003).
-Sykdomsvarighet > 24 mnd.
-Alvorlig, moderat/alvorlig, moderat og moderat/mild ME/CFS kan inkluderes.
-Alder 18-65 år.
-Undertegnet samtykke.
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| E.4 | Principal exclusion criteria |
-Patients with fatigue, who do not comply with the diagnostic (”Canadian”) criteria for ME/CFS.
-Disease duration < 24 months.
-Patients with mild ME/CFS.
-Patients with very severe ME/CFS (WHO function class IV), who are totally bedridden and in need of care.
-Patients where the workup uncovers other pathology as a possible cause of symptoms.
-Pregnancy or breast feeding. Positive pregnancy test.
-Previous cancer (except basal cell carcinoma of the skin or carcinoma in situ or cervix dysplasia).
-Previous long-term systemic treatment with immunosuppressive agents (Imurel, Sandimmun, Cellcept), except steroid treatments for e.g. obstructive lung disease or other autoimmune diseases like ulcerative colitis.
-Serious endogenous (primary) depression.
-Lack of ability to complete the study including follow-up.
-Reduced kidney function (creatinine > 1,5 x reference area).
-Reduced liver function (bilirubin > 1,5 x reference area, or transaminase > 1,5 x reference area).
-Known HIV-positivity, previous hepatitis B or hepatitis C, or reason to suspect other ongoing and clinically relevant infection. |
-Pasienter med fatigue, som ikke fyller de diagnostiske (”kanadiske”) kriterier for ME/CFS.
-Sykdomsvarighet < 24 mnd.
-Mild grad av ME/CFS skal ikke inkluderes.
-Svært alvorlig grad ME/CFS (sengeliggende og dels pleietrengende) skal ikke inkluderes.
-Pasienter der utredningen avdekker annen patologi som mulig årsak til symptomene.
-Graviditet eller amming. Positiv graviditetstest i serum.
-Tidligere kreftsykdom (unntatt basalcellecarcinom i hud eller carcinoma in situ/dysplasi i cervix uteri).
-Tidligere langvarig systemisk behandling med immunsuppressive midler (Imurel,
Sandimmun, Cellcept). Unntatt steroidkurer ved f.eks obstruktiv lungesykdom eller ved andre
autoimmune sykdommer, som for eksempel ulcerøs kolitt.
-Alvorlig endogen (primær) depresjon.
-Manglende evne til å gjennomføre studien inklusiv oppfølgning.
-Redusert nyrefunksjon (kreatinin > 1,5 x normalområdet).
-Redusert funksjon av lever (bilirubin > 1,5 x normalområdet, eller transaminaser > 1,5x normalområdet).
-Kjent HIV-positivitet, gjennomgått hepatitt B eller hepatitt C, eller holdepunkt for annen pågående aktiv og klinisk relevant infeksjon.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is recorded from the patient self-report form completed every two weeks during a follow-up period of 12 months after the first treatment. The variable Fatigue score is calculated every two weeks as the mean (scale 0-6) of the four symptoms: Fatigue, Post-exertional malaise, Need for rest and Daily function. The primary endpoint will be change in self-reported Fatigue score from baseline to mean scores during specific time intervals in the follow-up period (0-3, 3-6, 6-9 and 9-12 months), expressing the effect on the ME/CFS symptoms.
The Overall Response records the effect on the ME/CFS symptoms during 12 months after intervention start date. The Overall Response is not predefined to a specific time interval during the 12 months of follow-up, but the response must be recorded as moderate or major on the patient self-report form. Overall Response is defined as mean Fatigue score ≥ 4.5 for a minimum of 6 consecutive weeks for moderate response, and including a mean Fatigue score ≥ 5.0 for a minimum of 6 consecutive weeks for major response. The duration and sum of the various response periods during the follow-up period will be recorded. |
-Karakterisering av respons vil være basert på egenrapporteringsskjema som
fylles ut hver annen uke i en oppfølgningsperiode på 12 mnd. etter første behandling. Variabelen Fatiguescore registreres hver annen uke som gjennomsnittet av score (skala 0-6) for de fire fatigue-relaterte symptomene: ”Utmattelse etter anstrengelse”, ”Fatigue/Utmattelse”, ”Behov for hvile”, ”Funksjon i daglige oppgaver”. Det primære endepunktet vil være endring av egenrapportert Fatiguescore fra baseline til gjennomsnittsscore i hvert av tidsintervallene 0-3, 3-6, 6-9 og 9-12 mnd. i oppfølgningsperioden, som et uttrykk for effekt på symptombildet ved ME/CFS.
Overall Response vil bli angitt som effekt på symptombildet ved ME/CFS inntil 12 måneder etter start av intervensjon. Overall Response er uavhengig av hvilket tidsintervall responsen inntrer innenfor oppfølgningsperioden på 12 mnd., men responsen skal være registrert som moderat eller betydelig i henhold til pasientenes egenrapporteringsskjema. Kriteriet for Overall Response er definert som gjennomsnittlig Fatiguescore ≥ 4,5 i minst 6 sammenhengende uker for moderat respons, og inklusiv registrering av gjennomsnittlig Fatiguescore ≥ 5,0 i minst 6 sammenhengende uker for betydelig respons.
Enkeltstående responsperioders varighet og summen av slike responsperioders varighet innenfor oppfølgningsperioden blir registrert.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of changes in Fatigue scores from baseline at 0-3, 3-6, 6-9 and 9-12 months.
Evaluation of Overall Response at 12 months for the whole follow-up period.
|
Endring av Fatiguescore fra baseline registreres i intervallene 0-3, 3-6, 6-9 og 9-12 mnd.
Overall Response evalueres ved 12 mnd for hele oppfølgningsperioden. |
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| E.5.2 | Secondary end point(s) |
-SF-36 scores (”Physical health summary score”, ”Mental health summary score” and scores for eight SF-36 subdimensions) are analysed at baseline and at 3, 6, 9 and 12 months.
Changes will be analysed for the SF-36 ”Physical health summary score” (norm based), the SF-36-subdimension ”Physical Function” and changes in mean scores for the five SF-36 subdimensions ”Physical Function”, ”Bodily Pain”, ”Vitality”, ”Social Function” and ”General health”, from baseline to the predefined time points 3, 6, 9 and 12 months.
-Changes in physical activity measured by a Sensewear armband for seven consecutive days, before intervention and again between 7 and 9 months after intervention start date, possibly also after 11-12 months. Changes will be recorded for mean number of steps per 24 hours, max. number of steps per 24 hours, mean duration of moderate activity ≥ 3,5 METs per 24 hours, max. duration of moderate activity ≥ 3,5 METs per 24 hours.
-For the patients capable of completing a stress test, ergospirometry will be performed on two consecutive days, before intervention and repeated during the time interval 7-9 months after intervention start date, possibly also after 11-12 months. We will use a programmed ramp protocol with increasing work rate of 10 Watts/min, 15 Watts/min, 20 Watts/min, 25 Watts/min or 30 Watts/min, according to clinical assessment, gender and symptom severity. Oxygen uptake and exercise capacity (Watts) on day 2, at maximum work rate and anaerobic threshold are compared to the equivalent oxygen uptake and exercise capacity after 7-9 months, possibly also after 11-12 months. Changes from baseline (before intervention) to repeated test after 7-9 months (possibly also 11-12 months) are registered.
-Changes in physical activity measured by a Sensewear armband for seven consecutive days, before intervention and again between 7 and 9 months after intervention start date, possibly also after 11-12 months. Changes will be recorded for mean number of steps per 24 hours, max. number of steps per 24 hours, mean duration of moderate activity ≥ 3,5 METs per 24 hours, max. duration of moderate activity ≥ 3,5 METs per 24 hours.
-For the patients capable of completing a stress test, ergospirometry will be performed on two consecutive days, before intervention and repeated during the time interval 7-9 months after intervention start date, possibly also after 11-12 months. We will use a programmed ramp protocol with increasing work rate of 10 Watts/min, 15 Watts/min, 20 Watts/min, 25 Watts/min or 30 Watts/min, according to clinical assessment, gender and symptom severity. Oxygen uptake and exercise capacity (Watts) on day 2, at maximum work rate and anaerobic threshold are compared to the equivalent oxygen uptake and exercise capacity after 7-9 months, possibly also after 11-12 months. Changes from baseline (before intervention) to repeated test after 7-9 months (possibly also 11-12 months) are registered.
-”Total function” (scale 0-100, compared to healthy state) is recorded in the patient’s self-report form every two weeks. Changes are recorded from baseline to mean ”Total function” for time intervals 0-3, 3-6, 6-9 and 9-12 months after intervention start date.
-The Fatigue Severity Scale (FSS) will be completed at baseline, and at 3, 6, 9 and 12 months. Changes in FSS score from baseline and throughout follow-up will be recorded.
-The longest duration of lasting clinical response defined as lasting self-reported Fatigue score ≥ 4,5 (at least 6 consecutive weeks) during the 12 month follow-up period is recorded.
-The number of patients who have recorded response according to the response criteria and who show no sign of relapse (lasting Fatigue score ≥ 4,5 at 12 months follow-up), will be registered.
-Toxicity througout 12 months follow-up.
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-SF-36-scores (”Physical health summary score”, ”Mental health summary score”, samt score for de åtte SF-36-subdimensjonene) analyseres ved baseline samt ved 3, 6, 9 og 12 mnd. oppfølgning. Det analyseres for endring i SF-36-scores (”Physical health summary score”, ”Physical Function”, og gjennomsnitt av fem subdimensjoner (”Physical Function”, ”Bodily Pain”, ”Vitality”, ”Social Function” og ”General health”), fra baseline til hvert av tidspunktene 3, 6, 9 og 12 mnd. oppfølgning.
-Endring i fysisk aktivitetsnivå målt ved Sensewear-armbånd i 7 sammenhengende døgn, med registrering før intervensjon og med gjentatt registrering i tidsintervallet 7-9 mnd. oppfølgning, eventuelt med gjentatt registrering også ved 11-12 mnd. oppfølgning. Endring i gjennomsnittlig antall skritt per døgn, endring i maksimalt antall skritt per døgn, endring i gjennomsnittlig tid per døgn med aktivitetsnivå definert som moderat aktivitet tilsvarende ≥ 3,5 METs, og endring i maksimal tid per døgn med moderat aktivitet tilsvarende ≥ 3,5 METs, blir registrert.
-For pasienter som kan tåle slik belastning, utføres ergospirometri to påfølgende dager, før intervensjon og gjentatt i tidsrommet 7-9 mnd. etter start av intervensjon, eventuelt gjentatt også i tidsrommet 11-12 mnd. Det benyttes oppsett med programmert ramp-protokoll med økende belastning enten 10 Watt/min, 15 Watt/min, 20 Watt/min, 25 Watt/min, eller 30 Watt/min, avhengig av klinisk vurdering, kjønn og sykdomsgrad. Oksygenopptak og arbeidskapasitet (Watt) dag 2, ved maksimal belastning og ved anaerob terskel, brukes som sammenligning med tilsvarende oppnådd oksygenopptak og arbeidskapasitet etter 7-9 mnd., evt. også etter 11-12 mnd. Endring fra baseline (før intervensjon) til gjentatt undersøkelse etter 7-9 mnd. oppfølgning registreres, evt. også endring etter 11-12 mnd.
-”Totalt funksjonsnivå” (skala 0-100, sammenliknet mot helt frisk tilstand) registreres i pasientenes egenrapporteringsskjema hver annen uke.
Endring i ”Totalt funksjonsnivå” fra baseline til gjennomsnitt i hvert av tidsintervallene 0-3, 3-6, 6-9, og 9-12 mnd i oppfølgningsperioden registreres.
-Fatigue Severity Scale (FSS) fylles ut ved baseline, og etter 3, 6, 9 og 12 mnd. Endring i FSS score, fra baseline til registrering etter 3, 6, 9 og 12 mnd. blir registrert.
-Lengste varighet av sammenhengende klinisk respons definert som sammenhengende egenrapportert Fatigue score ≥ 4,5 (minst 6 sammenhengende uker) innenfor oppfølgningsperioden på 12 mnd. blir registrert.
-Andel av pasientene som har hatt respons etter kriteriene og som er uten tegn til tilbakefall av ME/CFS, definert som vedvarende Fatiguescore ≥ 4,5, ved 12 mnd. oppfølgning.
-Toksisitet gjennom 12 mnd. oppfølgning.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are evaluated at predefined timepoints or intervals during the follow-up period of 12 months. See E.5.2 for details on timepoints for each secondary endpoint. |
| Sekundære endepunkt evalueres ved predefinerte tidspunkt/tidsintervaller i oppfølgningsperioden på 12 mnd. Se detaljer under hvert endepunkt i pkt. E.5.2. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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