Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Alfasigma S.p.A., Via Ragazzi del ’99, n. 5, 40133 Bologna, Italy +39 0516489511 info.it@alfasigma.com
Pharmacotherapeutic group: Diagnostic agents, other diagnostic agents
ATC code: V04CX
Lumeblue is a delayed and extended-release multi-matrix (MMX) formulation in the form of tablets, each containing 25 mg of methylthioninium chloride as dried substance. The tablets are coated with an enteric coating that is stable at acidic pH (in the stomach) but breaks down at or above pH 7, normally achieved in the terminal ileum. Once the film coating has dissolved, the extended-release MMX formulation provides a slow release of the methylthioninium chloride dye, resulting in its homogeneous and prolonged dispersion on the surface of the colonic mucosa.
Methylthioninium chloride is known to be a “vital dye”, meaning “a dye or stain agent capable of penetrating living cells or tissues and not inducing immediate evident degenerative changes”. Methylthioninium chloride is taken up across the cell membrane into the cytoplasm of actively absorbing cells such as those found in the small intestine and colon, thereby staining the epithelia of those organs. Vital, absorptive dyes such as methylthioninium chloride, enhance the superficial structure of lesions by exploiting the different degrees of active mucosal stain uptake, highlighting contrast and therefore differences between cell types.
A total of seven clinical studies of Lumeblue have been conducted. The efficacy of this medicinal product was evaluated in one pivotal Phase 3 study (CB-17-01/06).
Study CB-17-01/06 was a Phase 3, multicentre, multinational, randomised, double-blind, placebocontrolled, parallel-group study to evaluate the adenoma or carcinoma detection rate in patients undergoing safety or surveillance colonoscopy high definition white light (HDWL) colonoscopy after colonic mucosal staining and contrast enhancing with Lumeblue tablets (compared to placebo tablets and gold standard HDWL colonoscopy alone). All subjects received 4 litres PEG-based bowel cleansing preparation starting in the late afternoon the day before the colonoscopy. The subjects were prescribed 3, 3, and 2x 25 mg tablets after the second, third, and fourth litre of bowel preparation, respectively. The subjects drank at least 250 mL of preparation every 15 minutes, so that the intake of study medicinal product and bowel cleansing preparation was completed 4 hours after commencement of the bowel cleansing preparation. The study comprised both a full dose (200 mg) arm and a low dose (100 mg) arm, which was included to assist blinding of the full dose active arm.
The primary endpoint of Study CB-17-01/06 was the ADR defined as the proportion of subjects with at least one histologically proven adenoma or carcinoma. Histologically proven adenoma was defined as Vienna grade 3 to 4.2, or a traditional serrated adenoma (TSA) or sessile serrated adenoma (SSA). Histologically proven carcinoma was defined as Vienna grade 4.3 to 5.b. The primary analysis population was defined as all randomised subjects who received at least one dose of study treatment and underwent colonoscopy, regardless of the completion status. The primary endpoint was analysed through a logistic regression with treatment, centre, age, gender, reason for colonoscopy, and number of excisions included in the regression model as fixed effects.
Primary endpoint results are provided in table 1 below.
Table 1. Efficacy results from study CB-17-01/06 – primary endpoint: ADR:
| Adenoma detection rate (ADR) | Lumeblue vs. placebo | ||
|---|---|---|---|
| Absolute value | 56.29% vs. 47.81% | ||
| Magnitude of effect | 8.48% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| OR without logistic regression | 1.41 | [1.09, 1.81] | 0.0099 |
| OR with logistic regression | 1.46 | [1.09, 1.96] | 0.0106 |
| OR with logistic regression excluding excisions as regression covariate | 1.51 | [1.15, 1.97] | 0.0027 |
The FPR was introduced to control for possible false positive study results, in that a high FPR would indicate a higher sampling rate in the Lumeblue group without a concomitant increase in ‘hit rate’ for detecting patients with positive lesions (adenomas or carcinomas). In this occurrence, a positive difference between Lumeblue and placebo (i.e., increase in the FPR) was hypothesised and a maximum threshold (non-inferiority margin) was set at 15%.
Table 2 and table 3 below present the FPR at both a subject and excision level. Lumeblue was statistically not inferior to placebo in FPR at both the subject and excision level. FPR at the subject level was numerically lower (-6.44%) in the treatment group than in the placebo group. At the excision level, the FPR of Lumeblue was numerically slightly greater (+2.63%) than placebo, however this was not considered clinically significant. These data demonstrate the effectiveness of Lumeblue at visualising lesions that were subsequently determined to be adenoma and carcinoma.
Table 2. Efficacy results from the study CB-17-01/06 – secondary endpoint: FPR (subject level):
| False positive rate (FPR) (subject level) | Lumeblue / placebo | ||
|---|---|---|---|
| Absolute value | 23.31% vs. 29.75% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| Magnitude of effect = difference in FPR (≥15% threshold for rejecting null hypothesis) | -6.44 | [-13.07, 0.19] | <0.0001 |
Table 3. Efficacy results from the study CB-17-01/06 – secondary endpoint: FPR (excision level):
| False positive rate (FPR) (excision level) | Lumeblue / placebo | ||
|---|---|---|---|
| Absolute value | 49.79% vs. 47.16% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| Magnitude of effect = difference in FPR (≥15% threshold for rejecting null hypothesis) | 2.63 | [-1.55, 6.81] | <0.0001 |
The tables below present further prespecified and post-hoc clinically meaningful endpoints from the pivotal Phase III study (CB17-01/06).
Table 4. Efficacy results from the study CB-17-01/06 – secondary endpoint: proportion of subjects with at least one adenoma:
| Proportion of subjects with at least one adenoma | Lumeblue / placebo | ||
|---|---|---|---|
| Absolute value | 55.88% vs. 47.18% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| Magnitude of effect = difference in proportion | 8.69 | [2.41, 14.98] | 0.0082 |
| OR without logistic regression | 1.42 | [1.10, 1.83] | 0.0082 |
Table 5. Efficacy results from the study CB-17-01/06 – exploratory endpoint: proportion of subjects with at least one non-polypoid lesion:
| Proportion of subjects with at least one non-polypoid lesion | Lumeblue / placebo | ||
|---|---|---|---|
| Absolute value | 43.92% vs. 35.07% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| Magnitude of effect = difference in proportion | 8.84% | [2.70, 14.99] | 0.0056 |
| OR without logistic regression | 1.45 | [1.12, 1.88] | 0.0056 |
| OR with logistic regression | 1.66 | [1.21, 2.26] | 0.0015 |
Table 6. Post hoc analysis: proportion of subjects with at least one non-polypoid adenoma or carcinoma:
| Proportion of subjects with at least one non-polypoid adenoma or carcinoma | Lumeblue / placebo | ||
|---|---|---|---|
| Absolute value | 25.77% vs. 19.21% | ||
| Adjusted odds ratio (OR) | Point estimate | 95% Confidence interval limits | p-value |
| Magnitude of effect = difference in proportion | 6.57% | [1.31, 11.82] | 0.0167 |
| OR without logistic regression | 1.46 | [1.08, 1.98] | 0.0167 |
Clinical studies show that methylthioninium chloride is well absorbed by the oral route, and rapidly taken up by the tissues. The majority of the dose is excreted in the urine, usually in the form of leucomethylthioninium chloride.
Following the oral administration of Lumeblue at a total dose of 200 mg (8 prolonged-release tablets, 25 mg each) in healthy subjects, peak plasma concentration (Cmax) was 1.15 ± 0.26 μg/mL, with a median time to peak concentration (Tmax) of 16 hours (10–24 hours). Absolute bioavailability was calculated to be approximately 100%.
Methylthioninium chloride inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, and induces CYP isozymes 1A2 and 2B6, but not 3A4, in human hepatocytes culture. In vitro, methylthioninium chloride acts as a substrate and weak inhibitor of P-gp, and as a substrate of OAT-3, OCT2, MATE1 and MATE2-K (see sections 4.4 and 4.5).
In a Phase 1 clinical study with 200 mg Lumeblue cumulative excretion of unchanged methylthioninium chloride at 60 hours postdose was approximately 39 ± 16% of the administered dose. The mean terminal half-life (T1/2) was determined to be approximately 15 hours.
In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safety and efficacy. There are limited data in patients ≥75 years of age.
Lumeblue was investigated in subjects undergoing screening or surveillance colonoscopy, with a mean age of 58.4 years (range 21 to 80 years) and 250 subjects at least 65 years of age, thus the subject population was representative of the intended clinical population, however there is limited data in patients ≥75 years of age. Overall, the safety profile of this medicinal product was broadly similar regardless of age. It is therefore proposed that neither warnings nor dose adjustments are required in respect of age.
Retrospective analysis of the safety dataset identifying subjects with some degree of renal impairment concluded that the incidence and pattern of TEAE in subjects receiving Lumeblue was consistent with the observed pooled safety database, and thus no warnings nor dose adjustments are required in respect to mild renal impairment. There are no data in patients with moderate to severe renal impairment, and therefore the medicinal product should be used with caution in patients with moderate to severe renal impairment (see section 4.2).
Retrospective analysis of the safety dataset identifying subjects with some degree of hepatic impairment concluded that the incidence and pattern of TEAE in subjects receiving Lumeblue was consistent with the observed pooled safety database, and thus no warnings nor dose adjustments are required in respect to mild to moderate hepatic impairment. There are no data in patients with severe hepatic impairment.
In repeat dose toxicity studies, with Lumeblue, no observed adverse effect level (NOAEL) was considered to be 600 mg/four days. Therefore, effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Methylthioninium chloride has been shown to be mutagenic in gene mutation assays in bacteria and mouse lymphoma cells, but not in vivo mouse micronucleus assay when administered intravenously at 62 mg/kg.
Some evidence of carcinogenic activity of methylthioninium chloride in male mice and rats, equivocal evidence of carcinogenic activity in female mice and no evidence of carcinogenic activity in female rats.
In animal studies, methylthioninium chloride produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis. As a precautionary measure, the use of methylthioninium chloride during pregnancy is contraindicated (see section 4.3).
Studies reported in literature suggest that exposure to methylthioninium chloride results in the reduction of sperm motility in vitro and teratogenic effects on embryo-foetal developmental effects in rats and rabbits. However, there were no consistent effects of methylthioninium chloride administration on reproductive system measures in male or female rats after 3-months oral treatment.
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