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Clinical Trial Results:
MISTRAL - Mistletoe therapy in primary and recurrent inoperable pancreatic cancer - A phase III prospective, randomized, double blinded, multicenter, parallel group, placebo controlled clinical trial on overall survival and health-related quality of Life

Summary
EudraCT number	2014-004552-64
Trial protocol	SE
Global end of trial date	10 Jan 2023

Results information
Results version number	v1(current)
This version publication date	28 May 2025
First version publication date	28 May 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

131016

ISRCTN number

US NCT number

NCT02948309

WHO universal trial number (UTN)

Sponsor organisation name

Karolinska University Hospital

Sponsor organisation address

Hälsovägen 13, K53, Huddinge, Sweden, 14186

Public contact

Clinnical Trial Unit, Medical Unit Upper Abdomen (former Center for Digestive Diseases, Karolinska University Hospital), +46 0707374261, kathrin.wode@regionstockholm.se

Scientific contact

Clinnical Trial Unit, Medical Unit Upper Abdomen (former Center for Digestive Diseases, Karolinska University Hospital), +46 0707374261, kathrin.wode@regionstockholm.se

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 Jan 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Jan 2023

Global end of trial reached?

Yes

Global end of trial date

10 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

Primary objective is to compare mistletoe therapy to placebo in the endpoint overall survival (time from randomization to death of any cause) in palliative patients with inoperable pancreatic cancer.

Protection of trial subjects

The trial was approved by the ethical board and the MPA in Sweden. All study personal was trained in GCP. The study was monitored on a regular basis. A data safety committee reviewed all SAE´s during the trial.

Background therapy

Standard of care for pancreatic cancer.

Evidence for comparator

Not applicable (placebo)

Actual start date of recruitment

01 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 290

Worldwide total number of subjects

290

EEA total number of subjects

290

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

199

85 years and over

Subject disposition

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Recruitment details

Between 7 June 2016 and 3 December 2021, 290 patients were recruited and randomized to 2 groups. The trial was conducted at 9 studysites in Sweden.

Screening details

n=924 patients were assessed for eligibility. n=634 were excluded due to - not meeting the eligibility criteria (n=257) - declined to participate (n=346) - reasons for ineligiblity not documented (n=31)

Period 1 title

Baseline period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Mistletoe (ME)

Arm description

injections with mistletoe extract (ME)

Arm type

Experimental

Investigational medicinal product name

Fermented Aqueous Extract (1:5) from Mistletoe Grown on Oak Trees

Investigational medicinal product code

Other name

Iscador Qu

Pharmaceutical forms

Injection, Solution for injection

Routes of administration

Subcutaneous use, Injection

Dosage and administration details

Treatment starts with low dose and is gradually increased by using 2 x 0,01 mg; 4 x 0,1 mg; 4 x 1 mg and 4 x 10 mg before reaching highest possible dose of 20 mg, which is to be continued for the rest of remaining time

placebo

Arm description

Isotonic solution of sodium chloride

Arm type

Placebo

Investigational medicinal product name

Isotonic solution of sodium chloride

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Injection , Subcutaneous use

Dosage and administration details

Treatment starts with low dose and is gradually increased using 2 x 0,01 mg; 4 x 0,1 mg; 4 x 1 mg and 4 x 10 mg before reaching highest possible dose of 20 mg, which is to be continued for the rest of remaining time in the trial.

Number of subjects in period 1	Mistletoe (ME)	placebo
Started	143	147
Completed	111	129
Not completed	32	18
Consent withdrawn by subject	31	18
Adverse event, non-fatal	1	-

Baseline characteristics

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Reporting group title

Mistletoe (ME)

Reporting group description

injections with mistletoe extract (ME)

Reporting group title

placebo

Reporting group description

Isotonic solution of sodium chloride

Reporting group values	Mistletoe (ME)	placebo	Total
Number of subjects	143	147	290
Age categorical
Units: Subjects
Adults (18-64 years)	31	54	85
From 65-84 years	110	89	199
85 and over	2	4	6
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	70 (65 to 74)	68 (60 to 76)	-
Gender categorical
males and females
Units: Subjects
Female	73	73	146
Male	70	74	144

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

For calculation of primary endpoint OS: no drop-outs

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomized in the trial

Subject analysis set title

PPT

Subject analysis set type

Per protocol

Subject analysis set description

As defined in the protocol, the following patients were excluded from the per-protocol (PP) analysis: ∙ those with at least one significant protocol deviation that was believed to have a potential impact on the efficacy outcome (OS) ∙ those who were only treated for <4 weeks or who received <66% of possible injections. A total of 219 participants (106 in the ME arm, 113 in the placebo arm) were included in the PP analysis. The following were excluded: ∙ severe protocol violations (2 in ME and 2 in placebo arm) ∙ no study treatment received (3 in ME and 4 in placebo arm) ∙ treatment period <4 weeks (19 in ME, 20 in placebo arm) and ∙ <66,6% of possible injections received (13 in ME and 8 in placebo arm).

Subject analysis sets values	Full analysis set	ITT	PPT
Number of subjects	290	290	219
Age categorical
Units: Subjects
Adults (18-64 years)	85	85	58
From 65-84 years	199	199	157
85 and over
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	69 (63 to 75)	69 (63 to 75)	70 (64 to 74)
Gender categorical
males and females
Units: Subjects
Female	144	144	110
Male	146	146	109

End points

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Reporting group title

Mistletoe (ME)

Reporting group description

injections with mistletoe extract (ME)

Reporting group title

placebo

Reporting group description

Isotonic solution of sodium chloride

Subject analysis set title

Full analysis set

Subject analysis set type

Full analysis

Subject analysis set description

For calculation of primary endpoint OS: no drop-outs

Subject analysis set title

ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

All subjects randomized in the trial

Subject analysis set title

PPT

Subject analysis set type

Per protocol

Subject analysis set description

Primary: overall survival

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End point title

overall survival

End point description

End point type

Primary

End point timeframe

from inclusion to end of study

End point values	Mistletoe (ME)	placebo	Full analysis set	ITT	PPT
Number of subjects analysed	143	147	290	290	219
Units: survival status
dead	135	136	271	271	201
alive	8	11	19	19	18

Attachments

Publication

Survival analyss comparing ME vs placebo

Statistical analysis description

The primary endpoint was survival, comparing ME vs placebo based on the ITT analysis set.

Comparison groups

ITT v Full analysis set

Number of subjects included in analysis

580

Analysis specification

Pre-specified

Analysis type

other ^[1]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.44

Variability estimate

Standard error of the mean

Dispersion value

0.123

Notes
[1] - The primary analysis was evaluated by Cox proportional hazards regression and testing the HR for overall survival in the ME versus the placebo arm, with additional study centre as covariate and planned chemotherapy (yes/no) as strata. The primary analysis was based on all eligble follow up for the ITT comparison group.

Adverse events

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Timeframe for reporting adverse events

From randomization to end of study participation

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

5.0

Reporting group title

mistletoe extract

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	mistletoe extract	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	29 / 143 (20.28%)	28 / 147 (19.05%)
number of deaths (all causes)	143	146
number of deaths resulting from adverse events	0	0
Vascular disorders
Thromboembolic event
subjects affected / exposed	3 / 143 (2.10%)	3 / 147 (2.04%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
occlusion biliary drainage
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
post surgical complications
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death NOS
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Disease progression
subjects affected / exposed	1 / 143 (0.70%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Allergic reaction
subjects affected / exposed	2 / 143 (1.40%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary edema
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
intoxiacation with drugs
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Arythmia
subjects affected / exposed	1 / 143 (0.70%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stroke
Additional description: inclusive transitoric ischemic attack
subjects affected / exposed	3 / 143 (2.10%)	2 / 147 (1.36%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 1
dysarthria
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Hemolysis
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Jaundice
subjects affected / exposed	0 / 143 (0.00%)	2 / 147 (1.36%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Ileus
Additional description: inclusive subileus
subjects affected / exposed	1 / 143 (0.70%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
upper gastrointestinal hemorrhage
subjects affected / exposed	1 / 143 (0.70%)	3 / 147 (2.04%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
diarrhea
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ascites
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
herniation disc
subjects affected / exposed	0 / 143 (0.00%)	1 / 147 (0.68%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Infections
subjects affected / exposed	16 / 143 (11.19%)	11 / 147 (7.48%)
occurrences causally related to treatment / all	0 / 14	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	mistletoe extract	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	46 / 143 (32.17%)	46 / 147 (31.29%)
Vascular disorders
Vascular disorders
Additional description: dizziness, flashes, hyptension, hypertension, stroke, thromboembolic event
subjects affected / exposed	11 / 143 (7.69%)	14 / 147 (9.52%)
occurrences all number	13	15
Surgical and medical procedures
Surgery
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences all number	1	0
Immune system disorders
Allergic reaction
Additional description: inclusive pseudoallergic reaction
subjects affected / exposed	3 / 143 (2.10%)	1 / 147 (0.68%)
occurrences all number	3	1
Respiratory, thoracic and mediastinal disorders
Respiratory disorders
Additional description: dyspnea, pulmory edema, thitis, sore throat
subjects affected / exposed	3 / 143 (2.10%)	4 / 147 (2.72%)
occurrences all number	3	5
Psychiatric disorders
Psychiatric disorders
Additional description: anxiety, confusion, insomnia
subjects affected / exposed	2 / 143 (1.40%)	1 / 147 (0.68%)
occurrences all number	2	1
Investigations
Elevation blood parameters
Additional description: elevation bilirubine, C-reactive protein, enzymes
subjects affected / exposed	1 / 143 (0.70%)	2 / 147 (1.36%)
occurrences all number	1	3
Injury, poisoning and procedural complications
Injury, poisoning, complications
Additional description: fracture, access complication, poisoning
subjects affected / exposed	2 / 143 (1.40%)	1 / 147 (0.68%)
occurrences all number	2	1
Cardiac disorders
cardiac symtoms
Additional description: fibrillation, failure, infarction, murmur, myocarditis, tachycardia
subjects affected / exposed	5 / 143 (3.50%)	3 / 147 (2.04%)
occurrences all number	5	3
Nervous system disorders
Nervous system disorders
Additional description: dizziness, heachache, neuropathya, stroke, syncope, TIA
subjects affected / exposed	5 / 143 (3.50%)	8 / 147 (5.44%)
occurrences all number	8	11
Blood and lymphatic system disorders
blood disorders
Additional description: anemia, hemolytic uremic thrombocytopenia, hemolysius, syndrome
subjects affected / exposed	4 / 143 (2.80%)	3 / 147 (2.04%)
occurrences all number	5	3
Eye disorders
Eye disorders
Additional description: diplopia, retinopathy, watery secretion
subjects affected / exposed	1 / 143 (0.70%)	1 / 147 (0.68%)
occurrences all number	1	2
Gastrointestinal disorders
Gastrointestinal symtoms
Additional description: oral mucositis, dry mouth, dyspepsia, nausea, vomiting, constipation, diarrhea, anorexia, gastropath
subjects affected / exposed	11 / 143 (7.69%)	15 / 147 (10.20%)
occurrences all number	14	21
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 143 (0.00%)	2 / 147 (1.36%)
occurrences all number	0	2
Skin and subcutaneous tissue disorders
Skin disorders
Additional description: eczema, local reaction, erythodysesthesia, pruritus, prupura, rash, skin induration, urticaria
subjects affected / exposed	12 / 143 (8.39%)	7 / 147 (4.76%)
occurrences all number	12	8
Renal and urinary disorders
Urinary disorders
Additional description: urinary retention
subjects affected / exposed	1 / 143 (0.70%)	0 / 147 (0.00%)
occurrences all number	1	0
Infections and infestations
Infections
Additional description: viarl, bacterial, fungus
subjects affected / exposed	24 / 143 (16.78%)	21 / 147 (14.29%)
occurrences all number	37	29
Metabolism and nutrition disorders
Metobolism disorders
Additional description: Hyperglycemia, hypokalemia, hyponatremia, acidosis
subjects affected / exposed	3 / 143 (2.10%)	2 / 147 (1.36%)
occurrences all number	3	2

More information

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Were there any global substantial amendments to the protocol? Yes

21 Nov 2016

Amendment to the ethical authority and MDA Sweden (26 june 2017). Addition of 2 new study sites incl PIs Addition of ancillary substudy with bloodsamples for biomarkers

28 Jun 2017

Amendment to the ethical authority: increase of accasions for bloodsampling from 4 to 5 and change of occasion when the bloodsamples are taken. Less blood/sample. New separate patients´ information and consent form for blood samples

22 Mar 2018

Amendment to the ethical authority Addition of 1 new study site incl PI

06 Dec 2019

Amendment ot ethical authority addition of 1 study site incl PI Possibility to check cause of death in the national "register for cause of death" (dödsorsaksregister)

19 Feb 2020

Amendment to the ethical authority Addition of 1 study site incl PI Increase of economical compenstation for study sites per included participant

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/38915151

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Clinical trials

Clinical Trial Results:
MISTRAL - Mistletoe therapy in primary and recurrent inoperable pancreatic cancer - A phase III prospective, randomized, double blinded, multicenter, parallel group, placebo controlled clinical trial on overall survival and health-related quality of Life

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: overall survival

Primary: overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: MISTRAL - Mistletoe therapy in primary and recurrent inoperable pancreatic cancer - A phase III prospective, randomized, double blinded, multicenter, parallel group, placebo controlled clinical trial on overall survival and health-related quality of Life

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: overall survival

Primary: overall survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
MISTRAL - Mistletoe therapy in primary and recurrent inoperable pancreatic cancer - A phase III prospective, randomized, double blinded, multicenter, parallel group, placebo controlled clinical trial on overall survival and health-related quality of Life